EFFICACY AND SAFETY OF ZOLEDRONATE VERSUS PLACEBO ON PAIN AT WEEK 12 IN PEDIATRIC PATIENTS WITH CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS (POMREP)
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
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.
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
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:
- To compare pain evolution between the two groups at weeks 4, 24 and 36 (pain at week 12 being the primary endpoint).
- To compare the use of NSAIDs, other analgesics and corticosteroids between the two groups during follow-up.
- 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.
- To compare biological inflammatory markers between the two groups at baseline and follow-up visits.
- To evaluate disease activity using the CNO Clinical Disease Activity Score (CNO CDAS) between the two groups at baseline and follow-up visits.
- To compare radiological disease activity on whole-body MRI between the two groups at baseline and follow-up visits using the mRINBO score.
- To assess treatment response using PedCNO30 and PedCNO50 score between the two groups at baseline and follow-up visits.
- To compare the rate of radiological remission (early remission at week 12; remission at weeks 24 and 36) between the two groups.
- To compare the rates of clinical and biological remission between the two groups at weeks 12, 24 and 36.
- To evaluate changes in health-related quality of life between the two groups at baseline and follow-up visits.
- To assess the impact on schooling (children) and work absenteeism (parents) between the two groups.
- To evaluate the safety and tolerance of zoledronate.
- To assess the cost-effectiveness of the strategy
Tipo de estudio
Inscripción (Estimado)
Fase
- Fase 2
Contactos y Ubicaciones
Estudio Contacto
- Nombre: Perrine DUSSER, MD, PhD
- Número de teléfono: +33145213254
- Correo electrónico: perrine.dusser@aphp.fr
Ubicaciones de estudio
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Val De Marne
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Le Kremlin-Bicêtre, Val De Marne, Francia, 94270
- Kremlin-Bicetre Hospital
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Contacto:
- Perrine DUSSER, MD, PhD
- Número de teléfono: +33145213254
- Correo electrónico: perrine.dusser@aphp.fr
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
- Niño
Acepta Voluntarios Saludables
Descripción
Inclusion Criteria:
- aged ≥4 and <17 years for whom:
- 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
- Written informed consent signed by the parents (the child may sign the consent if they wish, but their signature is not mandatory)
- 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:
- History of malignancy or current tumour
- History of seizure
- Current infectious osteomyelitis
- 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) ;
- Hypocalcemia ;
- Severe renal impairment with creatinine clearance < 35 ml/min ;
- Prior treatment with bisphosphonates and/or biotherapy within 6 months prior to inclusion.
- History of HIV, HBV, or HCV infection.
- Congenital or acquired prolonged QT interval (>0.44 seconds) on ECG.
- Clinically significant vertebral deformities, including vertebral fracture and/or angular kyphosis with risk of spinal cord compression.
- Suspected or confirmed tuberculosis.
- History of renal or hepatic insufficiency.
- Already enrolled in another interventional study.
- Pregnant or breastfeeding participants
- Not affiliated with the French social security system.
- Patient or legal guardians with limited understanding of the French language
- Serum 25-hydroxy vitamin D level <30 ng/mL at screening. Participants may be re-screened after correction of vitamin D deficiency.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Cuadruplicar
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
|---|---|
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Experimental: Zoledronate
Zoledronic acid, perfusion IV Baseline : 0.025 mg/kg ; Week 12 : 0.05 mg/kg ; Week 24 : 0.05 mg/kg
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Baseline : 0.025 mg/kg ; Week 4 : 0.05 mg/kg ; Week 6 : 0.05 mg/kg
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Comparador de placebos: NaCL 0.9%
NaCl 0.9%, perfusion IV Baseline Week 12 Week 24
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Baseline, Week 4 & Week 6
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Change in pain score from baseline to week 12
Periodo de tiempo: week 12
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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
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week 12
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Compare pain score (0-10 scale) evolution between groups at Weeks 4, 24 and 36
Periodo de tiempo: Week 4, 24 and 36
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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
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Week 4, 24 and 36
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Use of NSAIDs, other analgesics and corticosteroids between the two groups during follow-up.
Periodo de tiempo: Week 12, 24 and 36
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compare the use of NSAIDs, other analgesics and corticosteroids between the two groups during follow-up.
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Week 12, 24 and 36
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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
Periodo de tiempo: Week 12, 24 and 36
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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.
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Week 12, 24 and 36
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Biological inflammatory markers between the two groups at baseline and follow-up visits.
Periodo de tiempo: Week 12, 24 and 36
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compare biological inflammatory markers between the two groups at baseline and follow-up visits.
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Week 12, 24 and 36
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CNO Clinical Disease Activity Score (CNO CDAS)
Periodo de tiempo: Week 12, 24 and 36
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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.
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Week 12, 24 and 36
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Whole-body MRI disease activity assessed by the modified Radiological Index for Non-Bacterial Osteitis (mRINBO)
Periodo de tiempo: Week 12, 24 and 36
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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.
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Week 12, 24 and 36
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Proportion of participants achieving PedCNO30 response at week 36
Periodo de tiempo: week 36
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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%.
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week 36
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Radiological remission
Periodo de tiempo: Week 12, 24 and 36
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Compare the rate of radiological remission (early remission at week 12; remission at weeks 24 and 36) between the two groups.
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Week 12, 24 and 36
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Clinical and biological remission
Periodo de tiempo: Week 12, 24 and 36
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compare the rates of clinical and biological remission between the two groups at weeks 12, 24 and 36.
|
Week 12, 24 and 36
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Health-related quality of life assessed by the Pediatric Quality of Life Inventory (PedsQL)
Periodo de tiempo: week 36
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PedsQL total score ranges from 0 to 100.
Higher scores indicate better health-related quality of life.
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week 36
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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
Periodo de tiempo: week 36
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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.
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week 36
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Safety and tolerability of zoledronate, assessed by the incidence of adverse events and serious adverse events during the 36-week follow-up period
Periodo de tiempo: week 36
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week 36
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Incremental cost-effectiveness ratio (ICER) of zoledronate versus placebo at week 36
Periodo de tiempo: week 36
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Cost-effectiveness will be assessed by estimating the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY) gained.
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week 36
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Proportion of participants achieving PedCNO50 response at week 36
Periodo de tiempo: week 36
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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%.
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week 36
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Colaboradores e Investigadores
Patrocinador
Investigadores
- Investigador principal: Perrine DUSSER, MD, PhD, Assistance Publique - Hôpitaux de Paris
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Estimado)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
Otros números de identificación del estudio
- APHP220795
- 2023-506420-93-00 (Ctis)
Información sobre medicamentos y dispositivos, documentos del estudio
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