Médecins Sans Frontières (MSF/Doctors Without Borders) announced early closure of its phase 2/3 trial of a 6-month multidrug regimen for multidrug-resistant tuberculosis (MDR-TB) because an independent data safety and monitoring board (DSMB) determined that the drug combination in the study regimen was superior to current therapy, according to a press release.
The trial, called TB PRACTECAL, compared the current local standard of care with a six-month regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin. The interim analysis included 242 patients and the randomized controlled trial was conducted in sites in Belarus, South Africa, and Uzbekistan.
The preliminary data will be shared with the World Health Organization (WHO) soon and will also be submitted to a peer reviewed journal. If it withstands further reviews, as is anticipated, the trial would support the first solely oral regimen for MDR-TB.
In 2019, an estimated 465,000 people developed MDR-TB and 182,000 died. The global burden of TB at that time was about 10 million new cases, many with coexisting HIV.
Current treatment for MDR-TB lasts from 9 to 20 months and is complicated by the need for painful shots and toxic antibiotics. Side effects can include psychiatric problems from quinolones, isoniazid (INH), ethambutol, or cycloserine; deafness from aminoglycosides; and bone marrow suppression from linezolid, among other toxicities.
It's hoped that the shorter regimen will reduce toxicity and improve patient compliance. Poor adherence to treatment is a major driver of further drug resistance. Current regimens require up to 20 pills per day as well as daily injections.
In a prepared statement from MSF, David Moore, MD, MSc, London School of Hygiene and Tropical Medicine, United Kingdom, a member of the TB-PRACTECAL trial's steering committee, concluded, "The findings could transform the way we treat patients with drug-resistant forms of TB worldwide, who have been neglected for too long."
This good news is particularly welcome as, in the time of COVID-19, "an estimated 1.4 million fewer people received care for tuberculosis in 2020 than in 2019," according to the WHO. The drop, an overall 21% reduction in patients beginning treatment, ranged as high as 42% in Indonesia.
Although awaiting complete data, Madhukar Pai, MD, PhD, associate director of the McGill International TB Centre, McGill University, Montreal, Canada, shares Moore's enthusiasm. In an interview with Medscape Medical News, Pai compared MDR-TB to extensively drug-resisitant TB (XDR-TB).
"I'm excited about the possibility that these trial results might help shorten MDR-TB treatment to 6 months," said Pai. "That will be a huge relief to all patients battling drug-resistant disease. The 6-month BPaL regimen (bedaquiline, pretomanid, and linezolid) regimen works well in XDR-TB. So, I would expect the TB PRACTECAL regimen with one added drug (moxifloxacin) to work well in MDR-TB, which is less severe than XDR-TB. Between these two regimens, if we can bring down MDR and XDR treatment to 6 months, all-oral, that would be a huge advance."
The expense of bedaquiline has been a long-standing concern in the global health community. Janssen, a subsidiary of Johnson and Johnson, has reduced the price to $340 per 6-month treatment course for more than 135 eligible low- and middle-income countries.
Previously, the tiered pricing structure was different for low-, middle-, and high-income countries (US$900, $3,000, and $30,000, respectively). "The global TB community has asked Janssen to drop the price of bedaquiline to a level no higher than $32 per month — double the price at which researchers estimated bedaquiline could be sold for a profit." A major source of contention over pricing has been that there has been considerable public investment in the drug's development.
Pai concluded, "Bedaquiline is likely the most important drug in both 6-month regimens. We need to work harder to make bedaquiline, an excellent drug, more affordable and accessible."
While the full data is not yet publicly available, TB PRACTECAL was a randomized controlled multicenter study. The fact that enrollment was discontinued early by the DSMB suggests the efficacy data was compelling and that this completely oral regimen will become the standard of care.
Stone is an infectious disease specialist and author of Resilience: One Family's Story of Hope and Triumph Over Evil and of Conducting Clinical Research, the essential guide to the topic. You can find her at drjudystone.com or on Twitter @drjudystone.
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Cite this: Drug-Resistant TB Trial Stopped Early After Successful Results - Medscape - Mar 25, 2021.