A Phase 2 interventional study of Zoledronic Acid / Zoledronate 4 MG/100 ML Intravenous Solution and NaCL 0.9% Intravenous Solution in Osteomyelitis Chronic, sponsored by Assistance Publique - Hôpitaux de Paris. Not yet recruiting at 1 site in France. Open to participants aged 4 Years to 17 Years. Per ClinicalTrials.gov, last updated 2026-06-25.
Sponsored by Assistance Publique - Hôpitaux de Paris · Phase 2, Interventional, and Treatment
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 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.
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:
Exclusion Criteria:
Zoledronic acid, perfusion IV Baseline : 0.025 mg/kg ; Week 12 : 0.05 mg/kg ; Week 24 : 0.05 mg/kg
Drug: Zoledronic Acid / Zoledronate 4 MG/100 ML Intravenous Solution
NaCl 0.9%, perfusion IV Baseline Week 12 Week 24
Other: NaCL 0.9% Intravenous Solution
Baseline : 0.025 mg/kg ; Week 4 : 0.05 mg/kg ; Week 6 : 0.05 mg/kg
Baseline, Week 4 \& Week 6
Change in pain score from baseline to week 12
Change in standardized pain score (0-10 scale) from baseline to week 12, using Visual Analog Scale VAS 0-10/ 0 = no pain ; 10 = worst imaginable pain
Time frame: week 12
Compare pain score (0-10 scale) evolution between groups at Weeks 4, 24 and 36
Change in standardized pain score (0-10 scale) from baseline to week 4,24 \&36, using Visual Analog Scale VAS 0-10/ 0 = no pain ; 10 = worst imaginable pain
Time frame: Week 4, 24 and 36
Use of NSAIDs, other analgesics and corticosteroids between the two groups during follow-up.
compare the 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
Clinical manifestations will be assessed by physical examination at baseline and at weeks 12, 24 and 36. The proportion of participants presenting each manifestation (pain on palpation, arthritis, spinal deformity, dermatological manifestations, inflammatory bowel disease, growth impairment and pubertal delay) will be compared between groups.
Time frame: Week 12, 24 and 36
Biological inflammatory markers between the two groups at baseline and follow-up visits.
compare 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)
The Chronic Nonbacterial Osteomyelitis Clinical Disease Activity Score (CNO CDAS) is a composite disease activity score consisting of three components: (1) patient/parent pain assessment (0-10 visual analog scale), (2) patient/parent global assessment of disease activity (0-10 visual analog scale), and (3) physician assessment of the number of clinically active CNO lesions (0-10). Total scores range from 0 to 30, with higher scores indicating greater disease activity and a worse clinical condition. The CNO CDAS will be assessed at baseline and at weeks 12, 24, and 36.
Time frame: Week 12, 24 and 36
Whole-body MRI disease activity assessed by the modified Radiological Index for Non-Bacterial Osteitis (mRINBO)
The mRINBO score will be assessed on whole-body MRI at baseline and follow-up visits. The score incorporates the number of radiologically active lesions, the maximum lesion size (RALmax), extramedullary inflammatory changes, and chronic radiological changes. Higher scores indicate greater radiological disease activity. Whole-body MRI assessments will be performed at baseline and at weeks 12, 24, and 36.
Time frame: Week 12, 24 and 36
Proportion of participants achieving PedCNO30 response at week 36
PedCNO30 is defined as at least 30% improvement in at least three of five core variables, with no more than one variable worsening by \>30%.
Time frame: week 36
Radiological remission
Compare the rate of radiological remission (early remission at week 12; remission at weeks 24 and 36) between the two groups.
Time frame: Week 12, 24 and 36
Clinical and biological remission
compare the rates of clinical and biological remission between the two groups at weeks 12, 24 and 36.
Time frame: Week 12, 24 and 36
Health-related quality of life assessed by the Pediatric Quality of Life Inventory (PedsQL)
PedsQL total score ranges from 0 to 100. Higher scores indicate better health-related quality of life.
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
School and parental absenteeism will be assessed as the number of days missed from school by the child and the number of days missed from work by the parent during the previous 12 weeks. Data will be collected using the electronic patient-reported outcome (ePRO) diary and compared between treatment groups.
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
Incremental cost-effectiveness ratio (ICER) of zoledronate versus placebo at week 36
Cost-effectiveness will be assessed by estimating the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY) gained.
Time frame: week 36
Proportion of participants achieving PedCNO50 response at week 36
PedCNO50 is defined as at least 50% improvement in at least three of five core variables, with no more than one variable worsening by \>50%.
Time frame: week 36
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Assistance Publique - Hôpitaux de Paris