Tuberculosis, Central Nervous System

Regimen Would Decrease Duration of Treatment from Nine to Six Months LOS ANGELES, Dec. 07, 2023 (GLOBE NEWSWIRE) -- ACTG, a global clinical trials network focused on HIV and other infectious diseases, today announced the opening of the IMAGINE-TBM study (Improved Management with Antimicrobial AGents Isoniazid rifampiciN LinEzolid for TBM, also known as A5384). IMAGINE-TBM is a phase 2, randomized, open-label trial comparing a six-month regimen of high-dose rifampicin, high-dose isoniazid, linezolid, and pyrazinamide to the nine-month standard-of-care regimen for the treatment of tuberculous meningitis. Tuberculous meningitis is a life-threatening infectious disease that causes inflammation of the membranes that surround the brain and spinal cord. It is the most severe form of tuberculosis and is universally fatal when untreated. Even with standard-of-care treatment, outcomes are poor, with high rates of mortality and chronic disability among those who survive. While the global burden of tuberculous meningitis is unclear (due in large part to limited diagnostics), it is estimated to affect at least 100,000 people worldwide each year. “ACTG is especially excited about IMAGINE-TBM because it is an important step in addressing the paucity of data evaluating the best treatment approach for this devastating illness,” said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles. “ACTG has designed this study with investigators from around the globe with the goal of evaluating the potential benefit of the new regimen in diverse settings.” This multi-center trial will enroll 330 participants aged 15 years and older who have definite, probable, or possible tuberculous meningitis, including people living with and without HIV. Participants will be randomized in equal proportions to receive either the six-month regimen being studied or the nine-month standard of care: Those in the six-month regimen arm will receive rifampicin 35 mg/kg, isoniazid 10-15 mg/kg, linezolid 1200 mg, and pyrazinamide 25 mg/kg for eight weeks followed by rifampicin 35 mg/kg and isoniazid 10 mg/kg for 16 weeks (for a total of 24 weeks of study treatment)Those in the nine-month standard-of-care regimen arm will receive rifampicin 10 mg/kg, isoniazid 5 mg/kg, ethambutol 20 mg/kg, and pyrazinamide 25 mg/kg for eight weeks, followed by rifampicin 10 mg/kg and isoniazid 5 mg/kg for 28 weeks (for a total of 36 weeks of study treatment). Up to 15 mg/kg or a maximum of 900 mg daily of oral rifampicin will be permitted at the clinician’s discretion. “IMAGINE-TBM is ACTG’s first tuberculous meningitis protocol and will take place in locations around the world that have a high tuberculosis burden,” said IMAGINE-TBM protocol Co-Chair Felicia Chow, M.D., M.A.S., University of California, San Francisco. “IMAGINE-TBM is a tremendous opportunity to leverage ACTG’s diverse international sites to test a novel intervention for this devastating form of TB.” IMAGINE-TB will take place at 17 sites in Peru, Tanzania, Thailand, Vietnam, Mexico, Philippines, India, Brazil, Zimbabwe, Kenya, Malawi, and South Africa. It is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (which also funds ACTG) under award numbers UM1 AI068636, UM1 AI107716, and UM1 AI068634. “Our hope is that this regimen will result in improved outcomes among individuals compared to the current standard of care, while significantly decreasing the required length of treatment,” said IMAGINE-TBM protocol Co-Chair Vidya Mave, M.D., M.P.H., Byramjee Jeejeebhoy Government Medical College-Johns Hopkins University Clinical Research Site and Johns Hopkins Center for Infectious Diseases in India. “One of the top priorities for tuberculous meningitis research is optimizing treatment, which could have a profound impact on a population who has historically experienced abysmal outcomes.” IMAGINE-TBM is led by Drs. Chow and Mave and Kelly Dooley, M.D., Ph.D., Vanderbilt University (Vice-Chair). ACTG is led by Dr. Currier and Joseph J. Eron, M.D., University of North Carolina (ACTG Vice-Chair). For more information about IMAGINE-TBM, please visit clinicaltrials.gov. About ACTG ACTG is the world’s largest and longest running clinical trials network focused on HIV and other infectious diseases and the people living with them. It is funded by NIAID and collaborating NIH Institutes. Founded in 1987, ACTG conducts research to improve the management of HIV and its comorbidities; develop a cure for HIV; and innovate treatments for tuberculosis, hepatitis B, and emerging infectious diseases. It comprises thousands of dedicated researchers, staff, and community members who are pursuing research into novel treatments and cures for infectious diseases at hundreds of locations across four continents, with the ultimate goal of advancing science that meaningfully impacts the lives of the people we serve. Disclaimer: This content is solely the responsibility of ACTG and does not necessarily represent the official views of the NIH. Media Contact:Jenna Conley, ACTGjenna@conleycommunications.net

Findings in animal models show that a U.S. Food and Drug Administration (FDA)-approved antibiotic regimen for multidrug-resistant (MDR) tuberculosis (TB) may not work for TB meningitis. Findings from a Johns Hopkins Children's Center study in animal models show that a U.S. Food and Drug Administration (FDA)-approved antibiotic regimen for multidrug-resistant (MDR) tuberculosis (TB) may not work for TB meningitis. Studies in a small number of people also provide evidence that a new combination of drugs is needed to develop effective treatments for TB meningitis due to MDR strains. In a study published Dec. 29 in Nature Communications, the investigators showed that the FDA-approved regimen of three antibiotics -- bedaquiline, pretomanid and linezolid (BPaL) -- used for treating TB of the lungs due to MDR strains, is not effective in treating TB meningitis because bedaquiline and linezolid are restricted in crossing the blood-brain barrier, a network of cells that prevents the entry of germs and toxins into the brain. Tuberculosis, caused by the bacteria Mycobacterium tuberculosis, is a global public health threat. According to the World Health Organization, it is one of the leading killers by a single infectious agent. About 1%-2% of TB cases progress into TB meningitis, the worst form of TB, which leads to an infection in the brain that causes increased fluid and inflammation. "Most treatments for TB meningitis are based on studies of treatments for pulmonary TB, so we don't have good treatment options for TB meningitis," explains Sanjay Jain, M.D., senior author of the study and director of the Johns Hopkins Medicine Center for Infection and Inflammation Imaging Research. In 2019, the FDA approved the BPaL regimen to treat MDR strains of TB, specifically those that lead to pulmonary TB. However, there are limited data on how well these antibiotics cross the blood-brain barrier. In an effort to learn more, the research team synthesized a chemically identical and imageable version of the antibiotic pretomanid. They conducted experiments in mouse and rabbit models of TB meningitis using positron emission tomography (PET) imaging to noninvasively measure pretomanid penetration into the central nervous system as well as using direct drug measurements in mouse brains. In both models, researchers say PET imaging demonstrated excellent penetration of pretomanid into the brain or the central nervous system. However, the pretomanid levels in the cerebrospinal fluid (CSF) that bathes the brain were severalfold lower than in the brains of mice. "When we have measured drug concentrations in the spinal fluid, we have found that many times they have no relation to what's happening in the brain," says Elizabeth Tucker, M.D., one of the study's first authors and an assistant professor of anesthesiology and critical care medicine at the school of medicine. "This finding will change how we interpret data from clinical trials and, ultimately, treat infections in the brain." Next, researchers measured the efficacy of the BPaL regimen compared with the standard TB treatment -- a combination of the antibiotics rifampin, isoniazid and pyrazinamide -- used to treat drug-susceptible forms of TB. Results showed that the ability to kill bacteria in the brain using the BPaL regimen in the mouse model was about 50 times lower than the standard TB regimen after six weeks of treatment, likely due to restricted penetration of bedaquiline and linezolid into the brain. The bottom line, says Jain, is that the "regimen that we think works really well for MDR-TB in the lung does not work in the brain." In another experiment involving six healthy adults -- three men and three women between 20 and 53 years old -- at The Johns Hopkins Hospital, first-in-human PET imaging was used to show pretomanid distribution to major organs, according to researchers. Similar to what was seen in the mice, the study revealed high penetration of pretomanid into the brain or central nervous system with CSF levels lower than those seen in the brain. "Our findings suggest pretomanid-based regimens, in combination with other antibiotics active against MDR strains with high brain penetration, should be tested for treating MDR-TB meningitis," says Xueyi Chen, M.D., a pediatric infectious diseases fellow at the school of medicine and a study author, who is now studying combinations of such therapies. The investigators noted limitations, including the small quantities of the imageable version of pretomanid per subject (micrograms) used. However, current evidence suggests that studies with small quantities of a drug are a reliable predictor of the drug biodistribution. Along with Jain, authors from Johns Hopkins are Filipa Mota, Camilo A. Ruiz-Bedoya, Elizabeth W. Tucker, Daniel P. Holt, Patricia De Jesus, Martin A. Lodge, Clara Erice, Xueyi Chen, Melissa Bahr, Kelly Flavahan, John Kim, Mary Katherine Brosnan, Alvaro A. Ordonez and Robert F. Dannals. Another author is Charles A. Peloquin from the University of Florida. This study was funded by the U.S. National Institutes of Health R01-AI145435-A1 R01-AI153349R01-HL131829, R21- AI149760, and K08-AI139371.

The vaccine candidate VPM1002 shows its safety in a study with HIV- and non-HIV-exposed newborns. No other infectious disease has killed more people than tuberculosis. Currently, only one vaccine is available to prevent severe courses: Bacillus Calmette Guérin (BCG). However, it is not equally effective against all types of tuberculosis. Especially infants and immunocompromised patients are therefore in urgent need for more effective tuberculosis vaccines. A clinical trial in South Africa has now shown that the new vaccine candidate VPM1002, developed by Max Planck researcher Stefan H.E. Kaufmann and his team, is equally safe for newborns with and without HIV exposure and has fewer side effects compared to BCG. At least 20 million people worldwide suffer from tuberculosis, according to World Health Organization (WHO), with 10 million new cases every year and about 1.5 million deaths annually. The disease is caused by mycobacteria, which predominantly affect the lungs, but can also infect any other organ. Tuberculosis is particularly common in low income countries. Here, the WHO recommends that newborns be immunized against it as soon as possible. First used 100 years ago, the BCG vaccine against the disease contains attenuated pathogens of cattle tuberculosis. "We know that BCG can prevent so-called tuberculous meningitis and miliary tuberculosis in infants with a 75 to 86 percent effectiveness rate. But this is not the case for the most common form of the disease, pulmonary tuberculosis, in all age groups. Here, BCG is only insufficiently effective," explains Kaufmann, Emeritus Director at the Max Planck Institute for Multidisciplinary Sciences in Göttingen and the Max Planck Institute for Infection Biology in Berlin. Since the 1990s, the infection biologist and his team have been working on an improved next-generation vaccine, called VPM1002. To achieve this, the researchers genetically modified the attenuated BCG vaccine strain so that immune cells can better recognize the pathogens. "We developed VPM1002 in no small part to combine increased safety with improved efficacy for immunocompromised children," the Max Planck researcher reports. Vaccine candidate VPM1002 is safe The group of immunocompromised children includes, for example, HIV-exposed infants born to HIV-positive mothers. In a clinical trial in South Africa, an international research consortium including Kaufmann has now compared VPM1002 with BCG in HIV-exposed and non-HIV-exposed newborns. The study examined both the safety and the immune response induced -- called immunogenicity -- associated with the formation of immune cells and immunostimulatory proteins. The conclusion of the study: VPM1002 is safe in both HIV-exposed and non-HIV-exposed newborns, has fewer side effects than BCG, and elicits a similar immune response. In the randomized phase II double-blind study in South Africa, 416 eligible newborns were randomly selected and vaccinated before day 12 of life. 312 of them received VPM1002, and 104 received the BCG vaccine. As the study showed, VPM1002 triggered fewer vaccine-related adverse reactions than BCG. This was true for reactions occurring at the injection site, such as scarring and abscess formation, as well as enlargement of lymph nodes. This finding is important because local and regional reactions after vaccination are among the limitations of the BCG vaccine, Kaufmann points out. Newborns with or without HIV exposure showed similar immunogenicity with both vaccines. However, starting at six weeks of age, the BCG-triggered immune response was greater than in even younger infants. Phase III study investigates protection "Studies such as those described here examine a vaccine's immunogenicity, but not its protection. For the latter, we have already developed a larger phase III clinical trial and have successfully enrolled mothers with their newborns to participate. Now the clock is ticking," Kaufmann said. The infectious biologist expects initial results showing whether VPM1002 can provide comparable or better protection than existing BCG vaccines in about three years. In addition, the VPM1002 vaccine is currently evaluated in adults in two other phase III clinical trials in India for protection against tuberculosis. These trials are expected to be completed in 2023 and 2024, respectively. The Max Planck Society licensed the VPM1002 vaccine to the company Vakzine Projekt Management (VPM) in 2004. Starting in 2012, the company continued to develop the vaccine in collaboration with the Serum Institute of India, one of the world's largest vaccine manufacturers. "Serum Institute of India is giving access to a unique solution for tuberculosis elimination by detect-treat-prevent strategy. VPM1002 is a unique component of this strategy, and it will help in preventing infection and disease. The ongoing phase III trial is one of the key trials in order to strengthen our scientific rationale. Pleased to see that we have completed recruitment of all infants in such an important trial," said Umesh Shaligram, Executive Director R&D of Serum Institute of India.