TB-PRACTECAL study: First data on the treatment shortening study in MDR-TB
The results of the MSF-supported TB-PRACTECAL trial were presented at the International Union Against Tuberculosis and Lung Disease (IUTLD) conference in October 2021. It is a randomized, four-arm, open-label phase IIb study designed for non-inferiority and compared three different 6-month treatments with the WHO standard of care (SOC) for MDR/XDR-TB. The standard of care was not consistent throughout the study period due to changes in WHO recommendations since 2017. More than a third of the SOC group was treated with WHO short-term therapy over 9 months and just under two thirds received individualized therapy over approx. 18 months. Three quarters of the participants received bedaquiline. The already approved combination BPaL (bedaquillin, pretomanid, linezolid) was used in one of the experimental arms of the study and showed the lowest proportion of sputum culture conversions (47%) after 8 weeks of treatment compared to the other two experimental study arms with 77% (BPaL + moxifloxacin) and 67% (BPaL + clofazimine). The pivotal study for BPaL (NixTB) used 1200 mg linezolid and observed frequent adverse drug reactions (ADRs). In the PRACTECAL study, linezolid was used at a dose of 600 mg and it was left to the discretion of the study physician to reduce linezolid to 300 mg for better tolerability.
After reviewing the study data, an independent committee recommended the continuation of the study as a phase III with a combination treatment consisting of bedaquiline, pretomanid, linezolid and moxifloxacin (BPaLM). More than 60 people each received SOC and BPaLM. Recruitment was stopped in March 2021 on the advice of an independent committee due to the superiority of the experimental study arm. The proportion of culture conversions after 6 months was high in both arms. However, treatment success after 18 months of follow-up was significantly higher in the modified "intention to treat" (ITT) population with 89% after BPaLM than after SOC with 52%. The reason for the poorer treatment results with SOC was early treatment discontinuation, particularly in the first 8 weeks. The complete study protocol was completed by 57 participants in the BPaLM group compared to only 33 participants in the SOC group. The analysis of the "per protocol" population showed a treatment success rate of 97% (BPaLM) and 88% (SOC) and thus the non-inferiority of the study arm. ADRs were the most common reason for treatment discontinuation in the SOC group (n=16), in particular QT time prolongation (n=6), liver dysfunction (n=4) and hearing loss (n=2). In view of the unclear data on deaths in the approval studies of bedaquiline at the start of the study, the discontinuation criteria were narrowly defined in the interests of patient safety. Treatment failure was not observed in either group. 2 (3%) study participants died, both in the SOC group. "Lost to follow-up" was documented in only 3% of participants after 18 months of observation. Therapy support and directly observed therapy (DOT) were part of the study program and could also be maintained under the conditions of the SARS-CoV-2 pandemic through e.g. video observed therapy (VOT), telephone visits and home visits.
A shortened and better tolerated MDR-TB therapy has the potential to lead to fewer treatment discontinuations. After 18 months of follow-up, the new drug combination in the TB-PRACTECAL study showed promising treatment results with improved tolerability compared to SOC. However, these are preliminary study results and a complete evaluation of the data is still missing [1]. Nevertheless, a WHO representative at the "Union" conference already held out the prospect that the study data will in all likelihood be included in the planned update of the international recommendations for the treatment of MDR-TB. Updated recommendations for the treatment of patients in German-speaking countries will be published with the new S2k guideline in the coming months. In Germany, individualized MDR-TB therapy over 18 months based on the results of resistance testing is still recommended. Experience in the implementation of MDR-TB therapy and the structural prerequisites for using the diagnostic and therapeutic options should be available.
Changes to international recommendations and new study data are regularly summarized, commented on and, if necessary, classified for treatment in Germany under News on the DZK website.
Literature:
- Nyang'wa BT, Kloprogge F, Moore DAJ et al. Population pharmacokinetics and pharmacodynamics of investigational regimens' drugs in the TB-PRACTECAL clinical trial (the PRACTECAL-PKPD study): a prospective nested study protocol in a randomized controlled trial. BMJ Open 2021; 11: e047185. doi:10.1136/bmjopen-2020-047185.
