Efficacy and safety of zoledronate versus placebo on pain at week 12 in pediatric patients with chronic recurrent multifocal osteomyelitis resistant to non-steroidal anti-inflammatory drug

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Decision date (initial)

2026-05-26

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

French Ministry of Health and Solidarity

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

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 13

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 assess 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 rate 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 tolerance of zoledronate.
13. To assess the cost-effectiveness of the strategy

Conditions and MedDRA coding

Chronic recurrent multifocal osteomyelitis (CRMO)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Children or teenagers (≥ 4 years and <17 years)
2. Physician-confirmed diagnosis of CRMO according to Jansson’s criteria, with compatible MRI findings.Having lesions on MRI within 12 weeks prior to inclusion and clinically active disease defined by at least one of 2 criteria: patient/parent VAS (pain) superior or equal to 30/100 and/or physician VAS superior or equal to 30/100 after failure of at least 4 weeks of NSAIDs at a stable dose
3. Written informed consent signed by the parents (the child may sign the consent if they wish, but their signature is not mandatory)
4. Having had a dental review within 3 months prior to inclusion, with completion of any necessary invasive dental work before the first dose of zoledronate.

Exclusion criteria 17

1. History of malignancy or current tumour
2. Clinically significant vertebral deformities, including vertebral fracture and/or angular kyphosis with risk of spinal cord compression
3. Suspected tuberculosis.
4. History of renal or hepatic insufficiency.
5. Already enrolled in another interventional study.
6. Not affiliated with the French social security system.
7. Patient or legal guardians with limited understanding of the French language
8. History of seizure
9. Current infectious osteomyelitis
10. Contraindication to the study drug : Hypersensitivity to the active substance, to other bisphosphonates, or to any excipient (sodium hydroxide, hydrochloric acid for pH adjustment, water for injection) ;
11. Contraindication to the study drug : Hypocalcemia
12. Contraindication to the study drug : Severe renal impairment with creatinine clearance < 35 ml/min ;
13. Prior treatment with bisphosphonates and/or biotherapy within 6 months prior to inclusion.
14. History of HIV, HBV, or HCV infection.
15. ECG: check for congenital or acquired long QT > 0.44sec
16. Pregnant or breastfeeding participants
17. Serum 25-hydroxy vitamin D level <30 ng/mL at screening/baseline. These patients will not be randomized until correction of vitamin D deficiency and may be re-screened once vitamin D level is ≥30 ng/mL

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change in standardized pain score (0–10 scale) from baseline to week 12, assessed using an age-appropriate validated self-assessment scale on a 0–10 metric: the Faces Pain Scale–Revised (FPS-R, 0–10) for children aged ≥4 and <6 years, the pediatric visual analog scale (VAS, 0–10) for children aged ≥6 years who are able to do so, and the Numerical Rating Scale (NRS, 0–10) for children aged ≥8 years, depending on comprehension and feasibility.

Secondary endpoints 13

1. Pain assessment will be performed at baseline and weeks 4, 24 and 36 by the patient, using the same age-appropriate validated scales as for the primary endpoint. A reduction of pain ≥30% from baseline will be considered as clinically meaningful improvement, and a reduction of ≥50% as substantial improvement, assessed at weeks 4, 12, 24 and 36. Clinical remission is defined as complete disappearance of pain with a pain score of 0, assessed at weeks 12, 24 and 36
2. NSAIDs consumption will be measured by the average number of days with NSAIDs intake in the last 3 months. Other pain killers’ intakes or corticosteroids will also be recorded. Patients will receive a diary to collect information about pain medications. The consumption of NSAIDs and other pain killers will be assessed at weeks 12, 24 and 36.
3. Clinical signs will be compared between the two study groups at baseline, week 12, 24 and 36. The main clinical signs assessed during the physical exams of the patient will be: Pain on joint palpation / Arthritis / Spinal deformation / Extra-osseous manifestations: dermatologic manifestations (acne, palmoplantar pustulosis and psoriasis), synovitis, and inflammatory bowel disease / Staturo-ponderal growth and puberty
4. Assessment at baseline, week 12, 24 and 36 of inflammatory syndrome by clinicians using blood analyses to determine the frequency of children over the norm for: Rate of White Blood Cells (WBC> 10 000/mm3) / Rate of platelets (> 400 000/mm3) / Rate of C Reactive Protein (>5mg/l) / Sedimentation Rate (> 10mm) / And rate of pro-inflammatory cytokines
5. Disease activity will be assessed using the CNO Clinical Disease Activity Score (CNO CDAS), a composite score developed specifically for chronic nonbacterial osteomyelitis. The CNO CDAS includes the following three components: Patient (or parent) pain assessment on a 0–10 visual analog scale (VAS) / Patient (or parent) global assessment of disease activity on a 0–10 VAS / Clinician-reported count of clinically active CNO lesions (0 to 10)
6. Radiological assessment on whole-body MRI evaluated at baseline, week 12, 24 and 36: number of unequivocal lesions, number of new lesions since the previous MRI, and mRINBO score (including change from baseline)
7. Treatment response will be assessed using the PedCNO composite score at baseline, week 12, 24 and 36. Both PedCNO30 and PedCNO50 will be considered as secondary endpoints. PedCNO30 and PedCNO50 are defined as at least 30% and 50% improvement, respectively, in at least three out of five core set variables, with no more than one of the remaining variables deteriorating by more than 30% or 50%, respectively. / ESR / Number of radiological lesions / VAS physician / VAS patient/parents / CHAQ
8. Radiological remission, defined as MRI negativity (normalisation of MRI). Early remission will be assessed at week 12 and remission at week 24 and 36.
9. Clinical and biological remission, defined as the complete disappearance of pain and inflammatory syndrome. Clinical and biological remission will be assessed at week 12, 24 and 36.
10. Quality of life of children will be assessed at baseline and week 12, 24 and 36 using the PedSQL (Pediatric Quality of Life Inventory) questionnaire. It is a validated instrument with an international application designed to measure children’s health-related quality of life in four dimensions. The questionnaire will be completed by the child (self-report) if ≥ 8 years of age and by the parents (proxy-report) for younger children, with both reports collected when possible.
11. School and parental absenteeism will be defined by the number of days of absence from school or work for every period of 12 weeks. It will be measured at baseline, week 12, 24 and 36
12. Tolerance of ZA is defined by the occurrence of flu-like symptoms, headache, hypophosphatemia, hypocalcaemia.
13. Efficiency is defined as the incremental cost-effectiveness ratio in cost per quality-adjusted life-year gained.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Perrine DUSSER

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Perrine DUSSER

Locations

1 EU/EEA country · 12 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 19 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications