EFFICACY AND SAFETY OF ZOLEDRONATE VERSUS PLACEBO ON PAIN AT WEEK 12 IN PEDIATRIC PATIENTS WITH CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare auto-inflammatory bone disease that primarily affects children and/or adolescents at a median age of 10 years. Until now, there is no consensus regarding the treatment of CRMO. Non-steroidal anti-inflammatory drugs (NSAIDs) are considered the first line of therapy with remission in approximately 30% of cases. If unsuccessful, several treatments are tried in addition to NSAIDs, including bisphosphonates and anti-TNFs.

The effectiveness of bisphosphonates (including zoledronate) has been reported in clinical cases and/or retrospective series. They are said to be particularly effective in multifocal forms, mandibular and/or vertebral involvement, but no controlled trials have been conducted. Bisphosphonates have even been proposed as first-line therapy in spinal involvement. The only prospective study, is a phase II trial currently underway in Denmark to study the efficacy of zoledronate (NCT02594878) versus placebo in SAPHO (acronym, standing for Synovitis - Acne - Pustulosis - Hyperostosis - Osteitis) patients considered to be a very similar form of CRMO occurring in adults.

In this context, this study proposes to evaluate the efficacy of zoledronate compared to placebo in reducing pain at week 12 in children aged ≥4 and \<17 years with NSAID-resistant CRMO. Zoledronate will be administered in three escalating doses: 0.025 mg/kg at baseline (W0), 0.05 mg/kg at week 12 (W12), and 0.05 mg/kg at week 24 (W24). In addition to pain reduction, improvements in MRI findings will be observed, biological markers of inflammation, and quality of life in the zoledronate group. Although subjective, pain reduction remains the most widely used criterion in clinical practice to assess therapeutic efficacy. Zoledronate efficacy will therefore be assessed by the change in standardized pain score (0-10 scale) from baseline to week 12 as the primary endpoint, with additional pain assessments at weeks 4, 24, and 36 as secondary endpoints.

Main objective: To evaluate the efficacy of zoledronate, administered at increasing doses (0.025 mg/kg at baseline, 0.05 mg/kg at week 12, and 0.05 mg/kg at week 24; maximum dose 4 mg per infusion), versus placebo on the change in standardized pain score (0-10 scale) from baseline to week 12 in children aged ≥4 and \<17 years with NSAID-resistant CRMO.

Secondary objectives:

1. To compare pain evolution between the two groups at weeks 4, 24 and 36 (pain at week 12 being the primary endpoint). 2. To compare the use of NSAIDs, other analgesics and corticosteroids between the two groups during follow-up. 3. To compare clinical signs (pain on palpation, arthritis, spinal deformity, extra-osseous manifestations, growth and puberty) between the two groups at baseline and follow-up visits. 4. To compare biological inflammatory markers between the two groups at baseline and follow-up visits. 5. To evaluate disease activity using the CNO Clinical Disease Activity Score (CNO CDAS) between the two groups at baseline and follow-up visits. 6. To compare radiological disease activity on whole-body MRI between the two groups at baseline and follow-up visits using the mRINBO score. 7. To assess treatment response using PedCNO30 and PedCNO50 score between the two groups at baseline and follow-up visits. 8. To compare the rate of radiological remission (early remission at week 12; remission at weeks 24 and 36) between the two groups. 9. To compare the rates of clinical and biological remission between the two groups at weeks 12, 24 and 36. 10. To evaluate changes in health-related quality of life between the two groups at baseline and follow-up visits. 11. To assess the impact on schooling (children) and work absenteeism (parents) between the two groups. 12. To evaluate the safety and tolerance of zoledronate. 13. To assess the cost-effectiveness of the strategy

• Compare pain score (0-10 scale) evolution between groups at Weeks 4, 24 and 36 [Time frame: Week 4, 24 and 36]
• Use of NSAIDs, other analgesics and corticosteroids between the two groups during follow-up. [Time frame: Week 12, 24 and 36]
• Clinical signs (Number of participants presenting clinical manifestations of CRMO (pain on palpation, arthritis, spinal deformity, extra-osseous manifestations, growth impairment and pubertal delay) between the two groups at baseline and follow-up visits [Time frame: Week 12, 24 and 36]
• Biological inflammatory markers between the two groups at baseline and follow-up visits. [Time frame: Week 12, 24 and 36]
• CNO Clinical Disease Activity Score (CNO CDAS) [Time frame: Week 12, 24 and 36]
• Whole-body MRI disease activity assessed by the modified Radiological Index for Non-Bacterial Osteitis (mRINBO) [Time frame: Week 12, 24 and 36]
• Proportion of participants achieving PedCNO30 response at week 36 [Time frame: week 36]
• Radiological remission [Time frame: Week 12, 24 and 36]
• Clinical and biological remission [Time frame: Week 12, 24 and 36]
• Health-related quality of life assessed by the Pediatric Quality of Life Inventory (PedsQL) [Time frame: week 36]
• Number of days of school absenteeism (children) and work absenteeism (parents) recorded using the electronic patient-reported outcome (ePRO) diary, during each 12-week period [Time frame: week 36]
• Safety and tolerability of zoledronate, assessed by the incidence of adverse events and serious adverse events during the 36-week follow-up period [Time frame: week 36]