The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, today announced the launch of A5362 (CLO-FAST), a clinical trial studying a three-month clofazimine- and high-dose rifapentine-containing treatment regimen for people with drug-susceptible tuberculosis (TB). This is the first TB regimen based on preclinical evidence of effectiveness that is less than four-months long to be studied in a clinical trial. A5362 will evaluate the potential efficacy of clofazimine when combined with treatments that have been proven to be effective against TB.
Clofazimine achieves high tissue concentrations, which may contribute to sustained antimicrobial activity once treatment has ended. While it was first synthesized as an anti-TB drug, it has been primarily used (and well tolerated) in people with lepromatous leprosy over the past 50 years. Preclinical studies suggest that there may be powerful synergies in combining clofazimine with other TB treatments, which could substantively shorten TB treatment.
Shortening the duration of TB treatment remains one of the most important goals in global infectious disease research. For nearly the last half century, standard TB treatment required people to take medication for six months. The ACTG-sponsored A5349 recently demonstrated the potential of a four-month rifapentine-containing treatment regimen, a paradigm-shifting result. A5362 aims to build upon those findings by helping us better understand the activity of clofazimine and whether it may have the potential to further shorten TB treatment to three months."
ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles
A5362 is a phase 2c, open label, randomized study that is evaluating the efficacy, safety, and tolerability of adding clofazimine and substituting rifapentine for rifampin, compared to the six-month standard-of-care combination TB therapy. The trial will compare the early efficacy (time needed to convert TB sputum cultures to negative over 12 weeks) of a clofazimine- and rifapentine-containing regimen with the six-month standard TB regimen. It will also identify clinical treatment outcomes that will help determine whether the clofazimine-containing regimen should proceed to be studied in a large phase 3 clinical trial. A5362 will enroll a total of 185 participants and will follow them for 65 weeks. Participants will be randomized to the following groups:
- Arm 1 (experimental) will begin with a two-week loading dose of 300 mg of clofazimine and rifapentine (1200 mg/day) + isoniazid + pyrazinamide + ethambutol (PHZE) once a day, followed by six weeks of PHZE plus 100 mg of clofazimine once a day, followed by five weeks of rifapentine + isoniazid + pyrazinamide plus 100 mg of clofazimine once a day (for a total of three months of treatment).
- Arm 2 (standard of care) will begin with eight weeks of rifampin + isoniazid + pyrazinamide + ethambutol (RHZE) for 8 weeks, followed by 18 weeks of rifampin + isoniazid (for a total of six months of treatment).
- Arm C (subgroup evaluating pharmacokinetics) will replace the first four weeks of standard of care (Arm 2, above) with PHZE plus 100 mg of clofazimine (for a total of six months of treatment).
"Through the novel trial design of A5362, we aim to shed light on key characteristics of clofazimine treatment that we don't yet understand, while piloting an early assessment of a potential three-month treatment regimen for drug-susceptible TB," said protocol chair John Metcalfe, M.D., Ph.D., M.P.H., University of California, San Francisco. "We are hopeful that pairing it with other TB drugs with potent sterilizing activity will allow for a shorter course of treatment, thereby reducing the burden on the millions of people around the world who require TB treatment."
A5362 is led by Dr. Metcalfe, Samuel Pierre, M.D. (Les Centres Gheskio CRS, Haiti), and Kimberly Scarsi, PharmD, M.S. (University of Nebraska Medical Center). It is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and study drugs are supplied by the Global Drug Facility.