Abstract
BACKGROUND: Oral amoxicillin reduced pain and disability in patients with chronic Low Back Pain (cLBP) and vertebral endplate bone oedema (Modic changes type 1; MC1) in two randomised controlled trials (RCTs), providing evidence that cLBP with MC1 may be caused by a chronic bacterial infection of the disc. Disc tissue is poorly vascularised, and oral antibiotics will not achieve optimal antibacterial concentration. Linezolid has been formulated for intradiscal administration (PP353) to deliver effective antibacterial therapy while minimising systemic exposure. This trial aimed to establish whether PP353 is safe and has the potential to treat cLBP with MC1 or mixed MC1 and Modic changes type 2 (MC2). METHODS: The trial was a double blind, randomised, sham-procedure controlled phase 1b clinical trial in patients with cLBP of ≥6 months duration and MC1 or mixed MC1 and MC2 at a single lumbar level, aged 18-70 years, average Low Back Pain Numerical Rating Scale (LBP NRS) ≥ 4 on chronic pain medication or ≥ 6 if not, Roland Morris Disability Questionnaire-23 (RMDQ-23) score ≥9, low back pain greater than leg pain, and failure to adequately respond to standard of care. Interactive response technology randomly assigned participants 1:1 to PP353 (2 intradiscal doses) or placebo (2 sham procedures). The primary outcomes were the incidence of adverse events and the change in LBP NRS score at 12 months. Secondary outcomes were change in LBP NRS at intervening timepoints and change in RMDQ-23 and Oswestry Disability Index (ODI) (v2.1) at all timepoints, responder analyses ≥30% and ≥50% change from baseline and characterisation of the pharmacokinetics of two doses of PP353. The trial is registered with ClinicalTrials.gov (NCT04238676) and EudraCT (2018-004488-30), and the Universal Trial Number is U1111-1257-2567. FINDINGS: Between December, 2021, and December, 2023, 41 participants from sites in the UK, Spain, New Zealand and Denmark were recruited, with 40 participants receiving at least one dose of PP353 (20 participants) or placebo (20 participants) and having at least one post-baseline assessment of efficacy. 29 (72.5%) participants were female. PP353 and the intradiscal procedure were well tolerated, with no severe, life-threatening or disabling adverse events and no overall difference in adverse events from the sham procedure. At 12 months, a statistically significant and clinically meaningful difference between PP353 and placebo in mean group change from baseline in patient-reported pain (LBP NRS -3.36 vs -2.00; 95% CI -0.19, p = 0.028), using a predefined one-sided test, was observed. INTERPRETATION: Two intradiscal administrations of PP353 are well tolerated and could be an effective and minimally invasive, day case therapy for patients with cLBP associated with MC1 or mixed MC1 and MC2. FUNDING: Persica Pharmaceuticals Ltd funded the trial and was responsible for the conceptualisation, overall design, collation of data, decision to publish and the first draft of the manuscript.