CHronic Nonbacterial Osteomyelitis International Registry

NCT ID: NCT04725422

Last Updated: 2024-07-30

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 2000 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2018-08-01
• Study Completion Date: 2050-08-31

Brief Summary

The objective of the study is to establish a prospective disease registry for chronic recurrent multifocal osteomyelitis (CRMO)/chronic nonbacterial osteomyelitis (CNO) in order to investigate the natural history of the disease and the responses of patients to different clinical managements over 10 years.

Detailed Description

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease that mainly affects children and adolescents. Clinical presentations range from mild and sometimes limited unifocal disease to severe, chronically active or recurrent inflammation of multiple bones. The latter is referred to as chronic recurrent multifocal osteomyelitis (CRMO). Here we will use the term "CNO" to refer to the entire spectrum of this disease. CNO can be complicated by vertebral compression fractures, kyphosis, and leg length discrepancy when it is not recognized early or treated adequately. The diagnosis of CNO is made by excluding alternatives in the differential diagnosis including malignancy (leukemia, lymphoma, and primary or metastatic bone tumors), Langerhans cell histiocytosis, and infection. Clinical assessment in conjunction with serum inflammatory parameters and imaging studies, particularly magnetic resonance imaging (MRI), are crucial for the diagnosis and monitoring of disease activity of CNO1.

Because of significant variation in clinical treatment practices among pediatric rheumatologists, standardized treatment regimens (consensus treatment plans, CTPs) have been developed within the Childhood Arthritis and Rheumatology Research Alliance (CARRA), a North American organization comprised of pediatric rheumatologists and researchers, for CNO patients with an NSAID-refractory course and/or with active spinal lesions2. These CTPs provide an opportunity for pediatric rheumatologists to conduct comparative effectiveness research on CNO through prospective data collection. CRMO/CNO workgroup is comprised of pediatric rheumatologists from North America as well as international colleagues who are interested in collaborating in CNO research. Furthermore, risk factors of severe disease have been described by Wipff et al. based on a large retrospective cohort study3. Their results may be validated by an independent prospective cohort study. To date, there has been only one prospective study on CNO since its first description in 19724. Therefore, we propose to establish this international registry of patients with CNO to accomplish above goals. Long-term outcomes of CNO remains unknown due to the lack of prospective study. It has been estimated that at least 50% of CNO patients continue to need medications for CNO during adulthood. Our study will collect the clinical data and provide valuable data to characterize the long-term outcomes.

Conditions

Chronic Nonbacterial Osteomyelitis; Chronic Recurrent Multifocal Osteomyelitis

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

disease modifying anti-rheumatic drug, DMARD

1. Methotrexate 1 mg/kg (max 25 mg) PO or SQ weekly

2. Sulfasalazine 30 mg/kg (max 1000 mg) PO twice daily

3. Leflunomide 10-20 mg PO daily

Methotrexate

Intervention Type: DRUG

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Sulfasalazine

Intervention Type: DRUG

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Leflunomide

Intervention Type: DRUG

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

tumor necrosis factor inhibitor, TNFi

1. Adalimumab (subcutaneous) 10-40 mg SQ every other week

2. Etanercept (subcutaneous) 12.5-50 mg SQ every week

3. Infliximab (intravenous) 10 mg/kg (max 1000 mg) i.v. at week 0,2, 6 then every 4 weeks

4. Golimumab (subcutaneous or intravenous) 2 mg/kg (max 200 mg) at every 4 weeks

Etanercept

Intervention Type: DRUG

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Adalimumab

Intervention Type: DRUG

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Certolizumab

Intervention Type: DRUG

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Infliximab

Intervention Type: DRUG

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Golimumab

Intervention Type: DRUG

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

bisphosphonate

1. Pamidronate 1 mg/kg (max 90 mg) (intravenous)*:

Option 1: every month Option 2: 3 consecutive days every 3 months

2. Zoledronic acid 0.0125-0.05 mg/kg (max 4mg) (intravenous): every 3-6 months. * Both options may use lower dose of 0.5 mg/kg at the initiation of the treatment. All options allow concurrent use of NSAIDs.

Pamidronate

Intervention Type: DRUG

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Zoledronic acid

Intervention Type: DRUG

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

non-steroidal anti-inflammatory drugs

1. Naproxen 10 mg/kg (max 500 mg) PO twice daily

2. Indomethacin 1 mg/kg (max daily dose 150 mg) PO twice or three times daily

3. Meloxicam 0.1-0.3 mg/kg (max 15 mg) PO daily

4. Piroxicam 10-20 mg PO daily

5. Ibuprofen 10 mg/kg (max 800 mg) PO 3-4 times daily

NSAID

Intervention Type: DRUG

first-line treatment

Interventions

Methotrexate

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Intervention Type: DRUG

Sulfasalazine

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Intervention Type: DRUG

Leflunomide

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Intervention Type: DRUG

Pamidronate

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Intervention Type: DRUG

Zoledronic acid

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Intervention Type: DRUG

Etanercept

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Intervention Type: DRUG

Adalimumab

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Intervention Type: DRUG

Certolizumab

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Intervention Type: DRUG

Infliximab

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Intervention Type: DRUG

Golimumab

second-line treatment for children with CNO/CRMO after failure to respond to NSAIDs

Intervention Type: DRUG

NSAID

first-line treatment

Intervention Type: DRUG

Other Intervention Names

Azulfidine; areva; Aredia; enbrel; humira; cimzia; remicade, inflectra; simponi

Eligibility Criteria

Inclusion Criteria

• - Age at enrollment is equal to or younger than 21 years of age
• Presence of bone edema on STIR or T2 fat saturation sequence on MRI within 12 weeks of enrollment
• Whole body imaging evaluation (either WB MRI or bone scintigraphy)
• Bone biopsy to exclude infection or malignancy unless bone lesions follow typical distribution or there is IBD, psoriasis, or palmar plantar pustulosis

Exclusion Criteria

• - History of or current malignancy
• Current infectious osteomyelitis
• Contraindication to the selected treatment agent

• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Boston Children's Hospital, Boston, MA, USA

OTHER

Sponsor Role: collaborator

Hospital for Special Surgery, New York

OTHER

Sponsor Role: collaborator

Joseph M Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack, NJ, USA

UNKNOWN

Sponsor Role: collaborator

Riley Children's Hospital, Indianapolis, IN, USA

UNKNOWN

Sponsor Role: collaborator

University of North Carolina, Chapel Hill, NC, USA

UNKNOWN

Sponsor Role: collaborator

Royal Children's Hospital

OTHER

Sponsor Role: collaborator

Hacettepe University, Ankara, Turkey

UNKNOWN

Sponsor Role: collaborator

Bambino Gesù Children's Hospital, Rome, Italy

UNKNOWN

Sponsor Role: collaborator

University of British Columbia, Vancouver, BC, Canada

UNKNOWN

Sponsor Role: collaborator

Meyer Children's Hospital, Florence, Italy

UNKNOWN

Sponsor Role: collaborator

Mansoura University

OTHER

Sponsor Role: collaborator

University of Utah, Salt Lake City, UT, USA

UNKNOWN

Sponsor Role: collaborator

University of Iowa Carver College of Medicine, Iowa City, IA, USA

UNKNOWN

Sponsor Role: collaborator

Ann & Robert Lurie Children's Hospital of Chicago, Chicago, IL, USA

UNKNOWN

Sponsor Role: collaborator

Palacky University Olomouc Institute of Molecular and Translational Medicine, Olomouc, Czechia

UNKNOWN

Sponsor Role: collaborator

Alder Hey Children's NHS Foundation Trust Hospital, Liverpool, UK

UNKNOWN

Sponsor Role: collaborator

University of Calgary, Calgary, Alberta, Canada

UNKNOWN

Sponsor Role: collaborator

Seattle Children's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Yongdong (Dan) Zhao

Principle Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Seattle Children's Hospital

Seattle, Washington, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Yongdong (Dan) Zhao, MD, PhD

Role: CONTACT

crmoresearch@seattlechildrens.org

206-987-2000

Facility Contacts

Joshua Scheck, BS

Role: primary

crmoresearch@seattlechildrens.org

206-987-2000

References

Zhao Y, Wu EY, Oliver MS, Cooper AM, Basiaga ML, Vora SS, Lee TC, Fox E, Amarilyo G, Stern SM, Dvergsten JA, Haines KA, Rouster-Stevens KA, Onel KB, Cherian J, Hausmann JS, Miettunen P, Cellucci T, Nuruzzaman F, Taneja A, Barron KS, Hollander MC, Lapidus SK, Li SC, Ozen S, Girschick H, Laxer RM, Dedeoglu F, Hedrich CM, Ferguson PJ; Chronic Nonbacterial Osteomyelitis/Chronic Recurrent Multifocal Osteomyelitis Study Group and the Childhood Arthritis and Rheumatology Research Alliance Scleroderma, Vasculitis, Autoinflammatory and Rare Diseases Subcommittee. Consensus Treatment Plans for Chronic Nonbacterial Osteomyelitis Refractory to Nonsteroidal Antiinflammatory Drugs and/or With Active Spinal Lesions. Arthritis Care Res (Hoboken). 2018 Aug;70(8):1228-1237. doi: 10.1002/acr.23462. Epub 2018 Jul 12.

Reference Type: BACKGROUND

PMID: 29112802 (View on PubMed)

Zhao Y, Ferguson PJ. Chronic Nonbacterial Osteomyelitis and Chronic Recurrent Multifocal Osteomyelitis in Children. Pediatr Clin North Am. 2018 Aug;65(4):783-800. doi: 10.1016/j.pcl.2018.04.003.

Reference Type: BACKGROUND

PMID: 30031498 (View on PubMed)

Oliver M, Lee TC, Halpern-Felsher B, Murray E, Schwartz R, Zhao Y; CARRA SVARD CRMO/CNO workgroup. Disease burden and social impact of pediatric chronic nonbacterial osteomyelitis from the patient and family perspective. Pediatr Rheumatol Online J. 2018 Dec 14;16(1):78. doi: 10.1186/s12969-018-0294-1.

Reference Type: BACKGROUND

PMID: 30547806 (View on PubMed)

Beck C, Morbach H, Beer M, Stenzel M, Tappe D, Gattenlohner S, Hofmann U, Raab P, Girschick HJ. Chronic nonbacterial osteomyelitis in childhood: prospective follow-up during the first year of anti-inflammatory treatment. Arthritis Res Ther. 2010;12(2):R74. doi: 10.1186/ar2992.

Reference Type: BACKGROUND

PMID: 20433730 (View on PubMed)

Girschick H, Finetti M, Orlando F, Schalm S, Insalaco A, Ganser G, Nielsen S, Herlin T, Kone-Paut I, Martino S, Cattalini M, Anton J, Mohammed Al-Mayouf S, Hofer M, Quartier P, Boros C, Kuemmerle-Deschner J, Pires Marafon D, Alessio M, Schwarz T, Ruperto N, Martini A, Jansson A, Gattorno M; Paediatric Rheumatology International Trials Organisation (PRINTO) and the Eurofever registry. The multifaceted presentation of chronic recurrent multifocal osteomyelitis: a series of 486 cases from the Eurofever international registry. Rheumatology (Oxford). 2018 Jul 1;57(7):1203-1211. doi: 10.1093/rheumatology/key058.

Reference Type: BACKGROUND

PMID: 29596638 (View on PubMed)

Voit AM, Arnoldi AP, Douis H, Bleisteiner F, Jansson MK, Reiser MF, Weckbach S, Jansson AF. Whole-body Magnetic Resonance Imaging in Chronic Recurrent Multifocal Osteomyelitis: Clinical Longterm Assessment May Underestimate Activity. J Rheumatol. 2015 Aug;42(8):1455-62. doi: 10.3899/jrheum.141026. Epub 2015 May 15.

Reference Type: BACKGROUND

PMID: 25979713 (View on PubMed)

Wu EY, Oliver M, Scheck J, Lapidus S, Akca UK, Yasin S, Stern SM, Insalaco A, Pardeo M, Simonini G, Marrani E, Wang X, Huang B, Kovalick LK, Rosenwasser N, Casselman G, Liau A, Shao Y, Yang C, Mosa DM, Tucker L, Girschick H, Laxer RM, Akikusa JD, Hedrich CM, Onel K, Dedeoglu F, Twilt M, Ferguson PJ, Ozen S, Zhao Y. Feasibility of Conducting Comparative Effectiveness Research and Validation of a Clinical Disease Activity Score for Chronic Nonbacterial Osteomyelitis. J Rheumatol. 2023 Oct;50(10):1333-1340. doi: 10.3899/jrheum.2022-1323. Epub 2023 Jul 1.

Reference Type: BACKGROUND

PMID: 37399459 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

1232

Identifier Type: -

Identifier Source: org_study_id