CHronic Nonbacterial Osteomyelitis International Registry (CHOIR)
Conditions: Chronic Nonbacterial Osteomyelitis, Chronic Recurrent Multifocal Osteomyelitis
Sponsor: Seattle Children's Hospital

 
Principal Researcher: Yongdong (Dan) Zhao 
Protocol Version Number: v1.4 
Protocol Version Date: 2023.11.11 
 
 
 
 
 
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PROTOCOL TITLE: 
CHronic nonbacterial Osteomyelitis International Registry (CHOIR) 
PRINCIPAL INVESTIGATOR: 
Yongdong (Dan) Zhao, MD, PhD 
Pediatrics, Division of Rheumatology 
206-987-2682 
Yongdong.zhao@seattlechildrens.org 
 
Participating Sites Relying on SCH for IRB Review: 
University of Washington 
Boston Children’s Hospital 
 
 
 

 
Principal Researcher: Yongdong (Dan) Zhao 
Protocol Version Number: v1.4 
Protocol Version Date: 2023.11.11 
 
 
 
 
 
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Table of Contents 
 
 
1.0 
Objectives ......................................................................................................................................................... 3 
2.0 
Background ....................................................................................................................................................... 3 
3.0 
Inclusion and Exclusion Criteria ........................................................................................................................ 4 
4.0 
Study-Wide Number of Subjects ...................................................................................................................... 4 
5.0 
Study-Wide Recruitment Methods ................................................................................................................... 4 
6.0 
Multi-Site Research .......................................................................................................................................... 5 
7.0 
Study Timelines ................................................................................................................................................ 5 
8.0 
Study Endpoints ................................................................................................................................................ 5 
9.0 
Procedures Involved ......................................................................................................................................... 6 
10.0 
Data and Specimen Banking ............................................................................................................................. 6 
11.0 
Data Analysis/Management ............................................................................................................................. 7 
12.0 
Confidentiality .................................................................................................................................................. 7 
13.0 
Provisions to Monitor the Data to Ensure the Safety of Subjects .................................................................... 7 
14.0 
Withdrawal of Subjects .................................................................................................................................... 8 
15.0 
Risks to Subjects ............................................................................................................................................... 8 
16.0 
Potential Benefits to Subjects .......................................................................................................................... 8 
17.0 
Vulnerable Populations .................................................................................................................................... 8 
18.0 
Community-Based Participatory Research ....................................................................................................... 9 
19.0 
Sharing of Results with Subjects ....................................................................................................................... 9 
20.0 
Setting............................................................................................................................................................... 9 
21.0 
Resources Available ........................................................................................................................................ 12 
22.0 
Prior Approvals ............................................................................................................................................... 13 
23.0 
Recruitment Methods .................................................................................................................................... 13 
24.0 
Use of Social Media ........................................................................................................................................ 14 
25.0 
Local Number of Subjects ............................................................................................................................... 14 
26.0 
Provisions to Protect the Privacy Interests of Subjects .................................................................................. 14 
27.0 
Compensation for Research-Related Injury.................................................................................................... 15 
28.0 
Economic Burden to Subjects ......................................................................................................................... 15 
29.0 
Consent Process ............................................................................................................................................. 15 
30.0 
Process to Document Consent in Writing ....................................................................................................... 21 
31.0 
Drugs or Devices ............................................................................................................................................. 21 
32.0 
Good Clinical Practice ..................................................................................................................................... 21 
33.0 
References ...................................................................................................................................................... 21 
 
 

 
Principal Researcher: Yongdong (Dan) Zhao 
Protocol Version Number: v1.4 
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1.0 
Objectives 
Objective 
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 5 years. 
Aims 
Aim 1: To determine the clinical characteristics that are related to prognosis 
Aim 2: To compare the effectiveness of various clinical managements in practice 
setting. 
Aim 3: To characterize the long-term outcome of CNO 
2.0 
Background 
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 

 
Principal Researcher: Yongdong (Dan) Zhao 
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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 for up to 20 years and provide 
valuable data to characterize the long-term outcomes.  
3.0 
Inclusion and Exclusion Criteria 
Potential subjects will be identified by electronic medical record searches, clinic 
schedules, inpatient lists, and word of mouth recommendation. A member of the study 
team will review the potential subject’s medical records to confirm diagnosis, language, 
and care plan. If eligible, the caregiver and subject will be approached for participation. 
Eligibility will be confirmed with the caregiver verbally prior to obtaining informed 
consent.  
Inclusion Criteria 
- 
Presence of bone edema on STIR or T2 fat saturation sequence on MRI within 12 
weeks of enrollment (optional) 
- 
Whole body imaging evaluation (either WB MRI or bone scintigraphy) is optional 
- 
Bone biopsy to exclude infection or malignancy when indicated 
Exclusion Criteria 
- 
History of or current malignancy 
- 
Current infectious osteomyelitis 
- 
Contraindication to the selected treatment agent 
Adults who are unable to consent and lack a legal guardian, wards of the state, and 
prisoners will be excluded.  
Caregivers will be reporting about the subject’s medical history therefore they are not 
considered study subjects. 
As this is a multicenter international study, sites will use local language such as Turkish, 
German, Italian, etc.  
4.0 
Study-Wide Number of Subjects 
This is a multicenter registry with Seattle Children’s being the lead site. Due to the rarity 
of CRMO, we expect to accrue up to 2000 subjects at all sites that gain IRB approval.  
5.0 
Study-Wide Recruitment Methods 
Potential subjects at other sites may be enrolled in a similar manner as those enrolled at 
Seattle Children’s Hospital with subjects being identified by electronic medical record 
searches, clinic schedules, inpatient lists, and word of mouth recommendation. If local 

 
Principal Researcher: Yongdong (Dan) Zhao 
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sites allow, flyers and social media may also be used. The coordinating center, however, 
does not have control over the recruitment methods used at the participating sites. 
6.0 
Multi-Site Research 
Dr. Zhao is the study lead PI and is responsible for verifying that all sites have local IRB 
approval prior to study work being done. Dr. Zhao and/or his study team will be in 
charge of sending the most current versions of all regulatory documents to the sites 
once they are approved by Seattle Children’s IRB.  
Dr. Zhao will ensure that any study modifications are appropriately justified and receive 
Seattle Children’s IRB approval prior to being implemented. Any study modifications 
and/or study closure instructions will be outlined in an email that will be sent to all sites. 
Emails will be sent using the “Delivery Receipt” to ensure that sites receive the emails. 
Sites will be asked to reply to the email ensuring that they understand the 
modifications. If there are questions, Dr. Zhao or the study team will be made available 
for a telephone call.  
In addition, Dr. Zhao and his study team may plan to hold monthly phone calls to discuss 
study progress and interim results with the other sites. If a problem arises at sites, Dr. 
Zhao and the site PI will communicate via email and/or phone in order to resolve it.  
7.0 
Study Timelines 
Study participation will commence when informed consent is signed and ends 20 years 
thereafter or sooner, if subject transitions to other practices.  
We expect to approach all eligible subjects for participation therefore; recruitment and 
enrollment will be ongoing.  
At this time, we plan to analyze the data periodically per the study aims above. 
Additional analyses may be added as IRB modifications in the future. Results of de-
identified analyses may be shared with the clinical program team for quality 
improvement. 
8.0 
Study Endpoints 
Primary Endpoint: Determine the effectiveness of commonly used medications in SOP 
for patients with CNO.  
Clinical, laboratory and imaging results as well as PROs will be collected at each clinical 
visit after enrollment. Enrolled subjects will be stratified based on their past disease 
course, past treatment. Response to medication will be calculated based on previously 
described by Beck et al.5 and Zhao et al.2 at clinical visits prior to and after starting a new 
medication for comparison. Clinical disease activity score (CDAS) comprised of patient 
pain (0-10), patient global disease activity per report (0-10), clinical lesion count by 
physician, will be used to determine response. >=50% of reduction of CDAS is defined as 
favorable response.  

 
Principal Researcher: Yongdong (Dan) Zhao 
Protocol Version Number: v1.4 
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Secondary Endpoint: Determine the risk factors for patients with NSAID-refractory CNO.  
Patients will be classified as NSAID responders (significant improvement of pain, focal 
exam, ESR, CRP, imaging within 6 months of NSAIDs treatment), NSAID non-responders 
(requiring >6 weeks of systemic glucocorticoid, disease modifying anti rheumatic drugs, 
TNF inhibitors, bisphosphonate) based on treating physician’s assessment. Baseline 
demographic, clinical, laboratory, imaging results will be compared between two groups 
and odds ratio will be calculated. There is no safety endpoint because it is an 
observational study that does not pose any risk to subjects. 
9.0 
Procedures Involved 
This is a multicenter registry which involves the following procedures: 
• 
Prospective Chart review: will be performed to collect data when subjects and 
caregivers come to Seattle Children’s Hospital or a participating site for a 
scheduled clinic visit.  
• 
Retrospective Chart review: may also be performed for visits which occurred 
prior to informed consent, as long as these are already available in the medical 
record. 
• 
Safety Procedures: The required portions of the study are limited to ongoing 
review of the subject’s medical record, and therefore carry very minimal risk. 
• 
Questionnaires: Subject’s will be asked several questions that are not in their 
medical chart such as their demographics, complete medical history, 
medications, etc. 
No additional visits to the hospital will be requested as all study-related questionnaires 
will be done when subject comes to the site for a standard of care scheduled clinic visits. 
At Seattle Children’s, subjects typically come to clinic at the every 3-12 months interval 
after diagnosis, however, this may vary at participating sites. 
Access to standard care will not be delayed or precluded by participation in this registry. 
The Case Report Forms should be filled out by the participating site study team and data 
transcribed into the electronic database in a timely manner. Each site will be able to 
view their own data, while Seattle Children’s (coordinating center) will be able to view 
all of the uploaded limited data, which includes date of birth, partial postal close, date 
of death, and gender. If needed, for quality review, sites may be asked to send a scan of 
their completed Case Report Forms to the coordinating center using a secure file sharing 
systems or secure courier. 
10.0 
Data and Specimen Banking 
All data collected in the data collection sheets for this study will be kept permanently for 
both the coordinating center and the participating sites. The study data will be stored in 

 
Principal Researcher: Yongdong (Dan) Zhao 
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electronic databases secured by password on secure drives. Caregivers and/or subjects 
may request that data be removed from the database by writing to the principal 
investigator. Study data will be used for IRB/Ethics Committee-approved research 
regarding CNO only. 
Researchers from academic institutions (either SCH or other institutions) who want to 
use the de-identified study data (excludes date of birth, partial postal close, date of 
death, and gender) for other research questions must request the data from Dr. Zhao in 
writing, and provide proof of IRB approval for their project prior to receiving the data. 
Coded data without any linkers will be de-identified. Prior to release, a member of the 
study team will review the de-identified data to verify that no identifiers remain. A copy 
of any manuscripts, abstracts, or presentations resulting from a release of this kind will 
be required to be provided to Dr. Zhao. Dr. Zhao may refuse any request due to lack of 
scientific rigor, absence of appropriate data safeguards, lack of appropriate approvals, 
or other reasons.  
11.0 
Data Analysis/Management 
We will use multivariable linear mixed-effects regression models, with each treatment 
as the dependent variable and person as the random effect, to estimate the average 
treatment effect, as well as the mean difference between groups, and any interactions 
as relevant to the particular Aim. The model will adjust for age, gender, lesion number 
and past medication use. The FDR will be used separately in each Aim to account for 
multiple pair comparisons, with FDR<0.1 considered significant. 
Due to the rarity of CNO, we will enroll as many patients as possible to increase the 
power of this study to observe difference responses among treatments.  
A random percentage of subject visits will be selected throughout the course of the 
study for data quality checks. A second study team member will review the data for 
accuracy and address any errors that are identified. 
12.0 
Confidentiality  
Data will be kept in locked cabinets (paper forms) and/or in secure research drives and 
databases. Data will be identified with study codes and the link between study codes 
and subject identity will be kept separate from study data. Data being shared with other 
teams (see section 10) will be shared only as coded data without any linkers to preserve 
confidentiality.  
Local sites will have data that are linked to a person’s name, but the coordination center 
(Seattle Children’s) will only receive coded samples without any links. Data (e.g. scans of 
the Case Report Forms) being sent and shared with the coordinating center will be sent 
using secure file sharing systems (eg: DropBox, REDCap) or by sending electronic copies 
via secure courier (eg: password protected CD or USB drive sent via tracked FedEx). 
13.0 
Provisions to Monitor the Data to Ensure the Safety of Subjects 

 
Principal Researcher: Yongdong (Dan) Zhao 
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Due to the methods used to collect data, we do not expect adverse events related to the 
registry to occur. However, standardized severe adverse event (SAE) forms will be used 
to collect data for periodic update to the study group. Because this is an observational 
study, the medical decision is entirely determined by treating physician and not 
interfered by this registry.  
14.0 
Withdrawal of Subjects 
Subjects may be withdrawn if they become ineligible for inclusion, such as a mis-
diagnosis or subject becomes a foster child or prisoner. For subjects withdrawn for this 
reason, they (subject and/or caregiver) will be notified of the decision, and data 
collected prior to the withdrawal will be kept unless the caregiver otherwise requests 
that the data be removed from the study. 
If withdrawn by the study team, further data will not be obtained past the date of 
withdrawal, but existing data will be kept and analyzed.  
If withdrawn at the caregiver or subject’s request, they will be asked if they would like 
for existing data to be removed from the database. If not, then existing study data will 
be kept and analyzed. If yes, data will be removed from the database at the caregiver 
and/or subject’s request. In either case, additional data will not be collected. 
If withdrawn from the study, the decision regarding existing data will be documented 
and filed with the original source documents. If the data is to be removed from the 
study, this work will also be documented. 
15.0 
Risks to Subjects 
Rare, temporary, mild risk of emotional distress: It is possible that a subject or caregiver 
may experience emotional distress when completing the study-related questionnaires. 
Subjects and caregivers will be informed that they can skip any questions that they do 
not want to answer. In addition, there is a risk of breach of confidentiality. 
The study has no procedures that would carry unforeseeable risk to subject or risks to 
an embryo or fetus. 
16.0 
Potential Benefits to Subjects 
There is no benefit to participating in the study. This is a registry and does not provide 
additional treatment beyond what subjects would receive as part of their standard of 
care regimen.  
17.0 
Vulnerable Populations 
Cognitively Impaired Adults 
In the event that a cognitively impaired adult is enrolled, the subject will be withdrawn if 
they appear to be unduly distressed.  

 
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For adult subjects), a provider (MD, ARNP) of the research team will assess whether or 
not the subject is able to consent for himself/herself. This assessment may include but 
not be limited to: 1) results of prior educational or cognitive testing performed for 
medical care or education, 2) clinical assessment from interaction with the adult subject, 
3) presence of legal guardianship of another adult or agency on record. If an adult 
subject lacks a legal guardian, and if his/her capacity to consent is at all unclear, then 
the subject will not be enrolled. Subjects identified in this situation during the course of 
screening for the study may be referred to Social Work as part of their routine clinical 
care, as lack of a legal guardian is an important issue for a subject’s safety and well-
being during transition to adulthood. 
Children 
The research presents no more than minimal risk, as the research involves collection 
and analysis of data collected on paper forms.  The information collected will not affect 
the subject’s clinical care. 
Pregnant Women 
Data collection does not present any particular risk to pregnant women or the fetus, so 
they will be included in the research.   
18.0 
Community-Based Participatory Research 
N/A 
19.0 
Sharing of Results with Subjects 
Results of analyses performed for study purposes will not be shared with the subject or 
their caregiver(s).  
20.0 
Setting 
The research will take place at Seattle Children’s and the following participating sites:  
Sites within USA: 
Ann & Robert Lurie Children’s Hospital of Chicago, Chicago, IL, USA 
Boston Children's Hospital, Boston, MA, USA  
Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, USA 
Children's Hospital of Pittsburgh, Pittsburgh, PA, USA 
Children’s Hospital of The King’s Daughters, Norfolk, VA, USA 
Children’s Mercy Kansas City, MO, USA 
Colorado Children's Hospital, CO, USA 
Columbia University, New York City, NY, USA 

 
Principal Researcher: Yongdong (Dan) Zhao 
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Duke Children’s Hospital, Durham, NC, USA 
Floating Hospital for Children at Tufts Medical Center, Boston, MA, USA 
Goryeb Children's Hospital, Morristown, NJ, USA  
Hospital for Special Surgery, New York City, NY, USA 
Iowa Children's Hospital, Iowa City, IA, USA 
Joseph M Sanzari Children’s Hospital, Hackensack University Medical Center, 
Hackensack, NJ, USA 
Levine Children’s Hospital, Charlotte, NC, USA 
Lurie Nationwide Children’s Hospital, Columbus, OH, USA 
Mattel Children's Hospital UCLA, Los Angeles, CA, USA 
Massachusetts General Hospital, Massachusetts, WA, USA 
Mayo Clinic, Rochester, WA, USA 
Nationwide Children's Hospital, Columbus, OH, USA 
Riley Children’s Hospital, Indianapolis, IN, USA 
Seattle Children’s Hospital, Seattle, WA, USA 
Stanford Children’s Health, Stanford University, Palo Alto, CA, USA 
Stony Brook Children’s Hospital, Stony Brook, NY, USA 
Texas Children’s Hospital, Houston, TX, USA 
Tufts University, Boston, MA, USA 
University of California in San Francisco, San Francisco, CA, USA 
University of Iowa Carver College of Medicine, Iowa City, IA, USA 
University of Louisville, Louisville, KY, USA 
University of North Carolina, Chapel Hill, NC, USA 
University of Utah, Salt Lake City, UT, USA 
University of Vermont Medical Center, Burlington, VT, USA 
International sites: 
Asia & Pacific, 
Schneider Children’s Medical Center of Israel, Petach Tikva Israel and Sackler 
Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel  

 
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Nanjing Children’s Hospital, Nanjing, Jingsu State, China 
Royal Children’s Hospital, Melbourne, Australia 
Sidra Medical & Research Center, Ar-Rayyan, Qatar 
St. Petersburg State Pediatric Medical University, Saint Petersburg, Russia 
Africa, 
Red Cross Clinic, Cape Town, South Africa  
Mansoura University, Mansoura City, Egypt 
 
Europe, 
Palacky University Olomouc Institute of Molecular and Translational Medicine, 
Olomouc, Czechia 
Motol University Hospital, Prague, Czechia 
Bristol Royal Hospital for Children, Bristol, UK 
Hacettepe University, Ankara, Turkey 
Sağlık Bilimleri Üniversitesi Ümraniye Eğitim ve Araştırma Hastanesi, Istanbul, 
Turkey 
Children's Hospital Dresden, University Medical Center Carl Gustav Carus, TU 
Dresden, Dresden, Germany 
Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, 
Germany 
Pediatric Rheumatology, Olgahospital, Bismarckstr. 8, Stuttgart, Germany 
Vivantes Children's Hospital in Friedrichshain, Berlin, Germany 
Anna Meyer Children's Hospital, University of Florence, Italy 
Bambino Gesù Children’s Hospital, Rome, Italy 
Clinica Pediatrica, Università degli Studi di Brescia, Italy 
Dept. of Woman and Child Health, Padua, Italy 
Division of Rheumatology, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, 
Italy 
Gaetano Pini Hopital in Milano, Milan, Italy 
University of Genoa and Istituto Giannina Gaslini, Genoa, Italy 

 
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University of Palermo, Palermo, Italy 
Bristol Royal Hospital for Children & Royal National Hospital for Rheumatic 
Diseases, UK 
Central and North West London NHS Foundation Trust, UK 
Great Ormond Street Hospital, London, UK 
Institute of Translational Medicine, University of Liverpool, Liverpool, UK 
Alder Hey Children's NHS Foundation Trust Hospital, Liverpool, UK 
Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK 
Oxford University Hospitals NHS Foundation Trust, Oxford, UK 
Latin America, 
Departamento de Enfermedades Infecciosas e Inmunología Pediátrica 
Escuela de Medicina, Pontificia Universidad Católica de Chile 
North America, 
McMaster Children’s Hospital, Hamilton, Ontario, Canada  
The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada  
University of British Columbia, Vancouver, BC, Canada 
University of Calgary, Calgary, Alberta, Canada 
21.0 
Resources Available 
The study team will be comprised of a clinician who is involved in the provision of the 
routine clinical care of patients with CNO, and researchers who are involved in the 
collection of data for the study. The study team has dedicated office space at Seattle 
Children’s which may be used for the study data collection and analysis. Additional 
statistician support may be obtained to support future study analyses and these people 
would be added to the IRB staff list as a modification. 
Chart reviews may be performed by any member of the study team after they receive 
appropriate study training. In addition, clinician members of the study team will be 
available to any chart reviewer who has questions or needs additional support for data 
collection. 
Study team members are already in clinic and obtaining informed consent for this study 
will present a small increase in work over existing efforts. 
Recruitment may take up to 6 hours per week and chart review/data collection may be 
done over approximately 20 hours per month. 

 
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Existing study team member work stations, printers, and phones will be used to support 
the study. Additional materials may be purchased as needed. 
Training materials (eg: slide deck, handouts) will be provided with a copy of this protocol 
to study team members to review, either in self-directed learning or by individual or 
group training sessions.  
22.0 
Prior Approvals 
N/A 
23.0 
Recruitment Methods 
Potential subjects will be identified by electronic medical record searches, clinic 
schedules, inpatient lists, and word of mouth recommendation. Once identified, the 
study team member will review the medical record (if available) to confirm diagnosis, 
care plan, and language. If the subject seems eligible, then the subject and caregiver(s) 
will be approached for participation via phone, mail, email, or at their next clinic visit.  
In addition, potential subjects may self-identify through flyers posted on patient 
advocacy groups on social media (e.g. Facebook, Instagram, Twitter), and Seattle 
Children’s current research studies website and e-newsletters. 
Medical Chart 
Once a potential subject is identified, they may be mailed or emailed an 
introduction packet consisting of an introduction letter, consent and/or assent, 
and a response form before their next scheduled visit. If they do NOT want to be 
approached about the study at their next scheduled visit or via phone follow-up, 
the caregiver can indicate as such on the response form and can mail it back to 
the study team or respond via email. If the study team does not receive a 
response, a study team member may give the caregiver and potential subject a 
call to determine whether the subject and caregiver would like to hear more 
about the study, and will abide by the response given. If not reached via phone, 
the study team member will approach the potential subject and caregiver(s) in-
person at the next scheduled clinic visit or inpatient visit. 
Via mail/e-mail 
If possible, Seattle Children’s may send potential subjects and their caregivers 
an introduction letter, consent and/or assent forms, and a response form prior 
to a clinic visit, to allow the caregiver and subject to take time to consider the 
study. This would include study team contact information so the potential 
subject and caregiver(s) would have the choice of doing nothing, calling us, or 
sending the response form back via mail or e-mail to indicate their interest in 
the registry. 

 
Principal Researcher: Yongdong (Dan) Zhao 
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If interested, we may call the family to ask if there are questions and confirm 
their next scheduled visit appointment.  
Via in-person 
A member of the care team (eg: MD, ARNP, RN, etc.) will ask the family if they 
would like to speak to research. If yes, then the study team member will tell the 
family more about the research and complete the informed consent process if 
they are interested. If the family would like more time, they may complete the 
consent process by mail and return copies by fax, email, or mail to the study 
team. Please see section 29.0 below for details about the consent process. 
Via social media 
An information flyer will be posted on patient advocacy groups on social media 
which would include the phone number and email an interested subject could 
use to get in touch with the study team. We would then follow similar steps as 
those listed above.  
Subjects will not be paid for participation in the study. 
24.0 
Use of Social Media 
Study flyers on social media, such as Facebook, will be used as recruiting methods for 
the registry. The use of social media offers some key advantages compared to 
traditional recruitment methods (e.g. physician referral, TV and radio advertisement, 
etc) as it provides the ability to reach a diverse and broad audience, in particular, 
patients with CNO due to its rarity.  
To protect the privacy and confidentiality, a phone number and email will be provided 
for interested subjects to get in touch with the study team. In the posting, potential 
subjects will be encouraged to contact the study team rather than replying directly to 
the post.  
The materials used in social media as well as verbiage will be submitted to the IRB prior 
to implementation.  
25.0 
Local Number of Subjects 
Due to the rarity of CNO, we expect to accrue as many subjects as possible at Seattle 
Children’s with a minimum of at least 5 subjects. 
26.0 
Provisions to Protect the Privacy Interests of Subjects 
When approaching subject’s in-person, the study team will ask the caregiver and/or 
their caregiver if they would be interested in hearing about research. If yes, the study 
team will review the consent form with them. If no, the study team will thank the 
subject and/or caregiver for their time. The subject and their caregiver will be provided 
with the consent form in case they would like to read over it at their own pace at home.  

 
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It will be stressed that study participation is voluntary and they can say agree or 
disagree to take part in the registry without any repercussions to their care. 
27.0 
Compensation for Research-Related Injury 
The standard language for compensation applies; this study does not provide direct 
benefit to subjects. 
28.0 
Economic Burden to Subjects 
There are no costs to participating in this study. 
29.0 
Consent Process 
Whenever possible, informed consent/assent will be obtained when the subject 
expresses interest or attends a clinically scheduled telephone, telehealth, outpatient 
visit or inpatient stay. Consent/assent will be obtained in a private outpatient exam 
room, inpatient room, conference room, consultation room, or a setting where the 
subject is ensured privacy and is free from potential coercive influences. The study team 
member presenting the study to a potential subject will give the subject the opportunity 
to ask questions either in private or in the presence of their caregiver(s). The study team 
member will allow enough time to make an informed assessment of the subject’s 
comprehension of the details of the study.  Caregivers and subjects may take as much 
time as they need to decide if they would like to participate and may request a later 
follow up telephone conference with a member of the study team to provide informed 
consent. 
We will be following SOP HRP – 090 to conduct the consent conference. If a member of 
the study team who is obtaining informed consent is also the subject’s treating provider, 
then the provider will remind the family of the voluntary nature of the research, and will 
specifically indicate that whether or not the subject participates in the study, it will not 
affect the subject’s care.  
Consent discussions will take approximately 20 minutes to complete, but more time is 
available should the family need it. Follow-up to the consent discussion could be 
conducted remotely over the telephone, should the family need more time to think 
about participation. 
Non-provider members of the study team are available to obtain informed consent 
should any conflicts arise that may make it difficult for a family to decline participation 
in the study.  
Methods to confirm understanding will vary depending on the family’s preferences and 
skills, and may include verbal summaries, pictures, asking questions, repeat back of the 
content, and other methods. 
Participating sites will be responsible for their own consent documents.  The 
coordinating center will not provide templates. 

 
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When consenting remotely, every effort will be made to deliver the consent/assent 
forms to the individual by mail, fax, email well ahead of the scheduled conference so 
they have the opportunity to review the consent prior to the consent conference. The 
study team will verify the identities via the display of picture ID or the date of the 
subject’s last clinic/hospital visit and verify that the consent conference location is 
private to help ensure privacy and confidentiality. Next, the study team will review the 
consent/assent forms with the subject and/or legal guardian and will provide 
opportunities for questions to ensure comprehension of the details of the study. If the 
subject agrees to participate, the study team will ask the subject if they would like to 
electronically or physically sign the consent/assent form which are both identical in 
content. 
If the subject and/or legal guardian decides to electronically sign the consent/assent 
form, they may either use 1) DocuSign or 2) REDCap e-consent. An electronic copy of 
consent/assent forms will be saved under password-protected sharedrive. If there are 
addition information (i.e. new risk information), forms will be updated and existing 
subjects will be re-consented for continuous participation. 
To conform to the federal eSIGN law, the following will be added. 
Consent/Permission form statement: 
“If using electronic documentation: You agree this form and any later updates to this form 
and notices provided in connection with this study may be provided to you in an 
electronic version. You agree that you are able to electronically receive, review, and save 
a printed or electronic copy of this form containing your signature. We and you agree to 
electronically sign this form. We and you agree that our actions to electronically sign this 
form document your informed consent. We and you agree that our electronic signatures 
have the same meaning and effect as handwritten signatures. You understand that you 
can request a paper form if you would prefer to use a paper consent form.” 
 
Assent form statement: 
“If using electronic documentation (this means using something like a computer or phone 
instead of paper): You agree this form and any later updates to this form and notices 
provided in connection with this study may be provided to you in an electronic version. 
You agree that you are able to electronically receive, review, and save a printed or 
electronic copy of this form containing your signature. We and you agree to electronically 
sign this form. We and you agree that our actions to electronically sign this form 
document your assent. We and you agree that our electronic signatures have the same 
meaning and effect as handwritten signatures. You understand that you can request a 
paper form if you would prefer to use a paper assent form.” 
1) the study team will sign into Seattle Children’s DocuSign account through Seattle 
Children’s web portal. The study team will subsequently type in the emails of the study 
team, subject and/or legal guardian and assign the portions of the document to be 
signed by each party. After submitting this form, an email will be sent to the designated 
individual(s). The process of transmitting, receiving, and signing the consent/assent 
forms via DocuSign may take 5-10 minutes and no audio and/or video will be recorded. 

 
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The individuals receiving the email may sign the consent/assent form at the time of 
reception or save these documents to sign at a later time. The sent email will contain a 
link, which will allow individuals to navigate to the consent/assent form on DocuSign’s 
website. No sign up is required to sign the document. When signing the document, the 
individuals receiving the email are required to fill in their portions, which includes typing 
in their full name, current date, current time, and their signature. Computers or 
smartphones can be used to do this process. No additional or advanced knowledge 
besides knowing how to use a computer or smartphone is required to use DocuSign. 
Many young children may have their own smartphones and may use computers for 
portions of their school curriculum, thus young children and adults should have no 
difficulty with this process. The study team will be present for questions about signing 
the document(s) if the participant and/or legal guardian is signing the document(s) 
immediately. If the subject and/or legal guardian is signing the document later, the 
study team will be available by email or phone. After the subject and/or legal guardian 
have signed the consent/assent forms, the study team will fill out their assigned 
portions of the document and make a note on the consent form of when the consent 
conference took place and that it was by phone or video conference (so as to explain 
the difference in dates). After all parties have signed the document, DocuSign will 
provide a copy of the signed document to all parties. The study team will saved the copy 
of the signed document into the study’s directory in Seattle Children’s file share. 2) The 
REDCap e-Consent Framework provides standardized tools to obtain consent and store 
consent documentation with a certification screen and a storage function which 
automatically generates a PDF of the signed form stored within the project. The ‘Auto-
Archiver + e-Consent Framework’ survey option adds two things to the typical survey-
taking process. Before a participant completes the survey, an extra certification page is 
added to the end of the survey that displays an in-line PDF copy of the document in 
which they will be asked to confirm that all information in the document is correct. The 
survey will not be considered complete until they fulfill the certification step. Upon 
completion of the survey, a static copy of their responses in the form of a consent-
specific PDF will be stored in the project’s File Repository. The consent-specific PDF will 
have the values of the e-Consent Framework Options inserted at the bottom of each 
page in the PDF. 
These values (i.e., name, etc.) are added to the PDF as extra documentation of the 
identity of the person who is consenting. The participant will open the survey and read 
through the consent form. When they get to the bottom, they will have the opportunity 
to fill in their information and sign their name if they agree to participate. They will 
select “Next Page” and a read-only copy of the consent will be generated that they can 
review, download, and/or print. At the bottom of the page, they will need to select “I 
certify that all the information in the document above is correct, and I understand that 
signing this form electronically is the equivalent of signing a physical document.” Once 
this is selected they will be able to submit the survey/consent/assent. 

 
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The study team will use REDCap survey composition function and type in the emails of 
the subject and/or legal guardian and assign the portions of the document to be signed 
by each party. After submitting this form, an email will be sent to the designated 
individual(s). The process of transmitting, receiving, and signing the consent/assent 
forms via REDCap may take 5-10 minutes and no audio and/or video will be recorded. 
The individuals receiving the email may sign the consent/assent form at the time of 
reception or save these documents to sign at a later time. The sent email will contain a 
link, which will allow individuals to navigate to the consent/assent form on REDCap 
website. No sign up is required to sign the document. When signing the document, the 
individuals receiving the email are required to fill in their portions, which includes typing 
in their full name, current date, and their signature. Computers or smartphones can be 
used to do this process. The study team will be present for questions about signing the 
document(s) if the participant and/or legal guardian is signing the document(s) 
immediately. If the subject and/or legal guardian is signing the document later, the 
study team will be available by email or phone. After the subject and/or legal guardian 
have signed the consent/assent forms, REDCap will automatically save a copy of the 
signed document to the project. The study team will saved the copy of the signed 
document into the study’s directory in Seattle Children’s file share. 
If the subject and/or legal guardian decides to physically sign the consent/assent forms, 
the study team will either send the forms by mail to the designated physical address or 
by email to the provided email addresses. After signing the forms, the subject and/or 
legal guardian will send it back to the study team via mail or scan/photograph the signed 
form to forward by email attachment. The research team member will sign the form on 
the day that it is received and make a note on the consent form of when the consent 
conference took place and that it was by phone or video conference (so as to explain the 
difference in dates). 
Non-English Speaking Subjects 
At Seattle Children’s, subjects who speak other languages will be approached for the 
study. Some subject-facing study materials have been translated into Spanish, Arabic, 
Bengali, Russian and simplified Chinese and submitted as a study modification following 
initial IRB approval of English documents. Additional subject-facing study materials will 
be translated and submitted as study modifications when available. An interpreter (in-
person, phone, or tablet) will be made available during the visit.  External sites will be 
responsible for obtaining their own translations. 
Partial Waiver of HIPAA 
We are requesting a waiver HIPAA for pre-screening purposes only. This waiver would 
allow us to review the medical record prior to approaching potentially eligible subjects 
for participation to confirm diagnosis, language, and care plan. This approach would 
allow us to only approach subjects for participation who are likely to be eligible, and 

 
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would prevent the study team from causing an unnecessary burden for families who are 
not eligible for the study.  
Identifiable screening data will only be kept intact until the eligibility has been 
confirmed. If ineligible, the reason for ineligibility will be retained as coded data for 
analysis purposes, but will not be identifiable (eg: coded without any linkers). If eligible, 
this data will be incorporated into data collected on the data collection form. Electronic 
screening data will be kept on secure research shared drives which are accessible to the 
study team and/or on secure electronic databases (eg REDCap) which limits access by 
username and password. Paper screening data will be kept in secured offices in secure 
cabinets. Paper screening data for ineligible subjects will not have any identifiers on the 
worksheet, only study codes. PHI accessed or collected during screening will not be 
reused nor disclosed to other people or entities except as required by law or research 
regulations. Without the PHI (medical record number and name), we would be unable 
to access the information needed to confirm eligibility. Without the waiver of HIPAA, 
completing the HIPAA authorization would confer a larger burden to families of 
ineligible subjects than the eligibility review itself. 
Waiver of consents for adults who have transitioned care out of Seattle Children’s 
Hospital 
Due to the rarity of this disease, we need to maximize data collection on all eligible 
patients including those we may have not been able to consent during their care within 
Seattle Children’s. Criteria for this group are: age of 18 or older at the time of data 
collection, never consented to CHOIR, and confirmed transition as documented in 
clinical or other note. No patient contact will be initiated, and no questionnaire will be 
administered. The research could NOT practicably be carried out without the waiver or 
alteration because this group of patients might have moved or not reachable due to 
outdated contact information within our system. All eligible patients must also be 
included in the study for the results to be meaningful. Obtaining consent from patients 
whose data will be analyzed is impracticable due to the number of patients involved, the 
timespan over which the data was generated, and the subsequent movement of those 
patients. The waiver or alteration will NOT adversely affect the rights and welfare of the 
subjects because there is no intervention or patient contact required. Only de-identified 
data will be collected from previous care notes. Information that could put subjects or 
their families at harm (e.g., affect eligibility for insurance, employability, stigmatization) 
or that would alter or affect the subject’s care will not be collected.  Any publication of 
presentation of research results would be done in a manner that would never reveal an 
individual’s identity either directly or indirectly. 
Subjects who are not yet adults (infants, children, teenagers) 
Subjects enrolled at Seattle Children’s Hospital under the age of 18 will be considered 
minors for this study and must have a legal caregiver provide informed consent in order 

 
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to participate. Parental permission will be obtained by one caregiver, as this is a minimal 
risk study without prospect of benefit. At all other participating sites, the local site PI will 
document consent, assent, and parental permission based on their local laws and 
regulations.  
Assent will be obtained from subjects who are age 7 years or greater and have cognitive 
function and decision making skills function equivalent to a 7 year old or better. 
Therefore, a subject older than 7 years who has a developmental delay, but is still 
functioning on par with a typically developing 7 year old will still be approached for 
assent. Functional level will be assessed by the caregiver(s) and investigator if this is in 
question. If there is not consensus between caregiver(s) and investigator in this regard, 
then the subject will be approached for assent. Assessment may be done using different 
sources of information, including caregiver(s)’ report of subject’s typical ability at home, 
available testing performed for medical or educational care, provider’s assessment of 
the subject’s ability. 
For subjects age 7 – 12, assent will be documented by the subject signing his/her name 
on the simple assent form. Subjects age 13 – 17, will sign the assent/consent form.  If 
cognitively able to assent but physically unable to sign, then assent will be obtained 
verbally or by the subject’s usual communication method, and witnessed by an adult 
person who is not the study team member obtaining consent (eg: other Children’s staff 
member). The witness shall sign their name on the assent form.  
For all subjects who are eligible to provide assent, the study team member will review 
the assent form in person with the subject. This may include reading portions of the 
form aloud, summarizing portions of the form, or other methods to explain the decision 
to the subject. If the subject agrees to participate, then the assent form will be signed as 
above. 
Subjects who reach the age of majority and are their own legal guardian as of the 18th 
birthday will be re-approached for consent. If they decline ongoing participation, their 
existing information will be kept, but further data collection will be stopped.  
Subjects who reach of the age of majority and are not their own legal guardian will be 
re-consented by their legal guardian unless the legal guardian has a court order that 
extends their guardianship past the age of majority.  
If the child who reaches the age of majority is legally their own guardian, but is 
cognitively unable to provide informed consent, then they will not be eligible to 
continue in the study, and their participation will be complete. In this case, existing data 
will be kept, but further data collection will be stopped. 
Cognitively Impaired Adults 
Cognitively impaired adults are eligible to participate only if they have a legal guardian 
who is able to provide informed consent. People who are unable to provide informed 

 
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consent but lack another legal guardian will not be enrolled. If a cognitively impaired 
adult is functioning at the level of a typical 7 year old or better, then assent will be 
obtained and documented as above. 
Caregivers of eligible children who themselves have cognitive impairment who are still 
their child’s legal guardian will be able to provide consent if they are able to understand 
the consent process and make a decision. If this is at all unclear, then the child will be 
considered ineligible and the child will not be enrolled. 
Adults Unable to Consent 
HRP-013 will be followed when enrolling adults who are unable to consent.  
Consent for use of HUD 
N/A 
30.0 
Process to Document Consent in Writing 
We will be following “SOP: Written Documentation of Consent (HRP-091).” 
31.0 
Drugs or Devices 
N/A 
32.0 
Good Clinical Practice 
N/A 
33.0 
References 
1. Hofmann SR, Schnabel A, Rosen-Wolff A, Morbach H, Girschick HJ, Hedrich CM. Chronic 
Nonbacterial Osteomyelitis: Pathophysiological Concepts and Current Treatment Strategies. J 
Rheumatol 2016. 
2.  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 S, Li SC, 
Ozen S, Girschick H, Laxer RM, Dedeoglu F, et al. Consensus Treatment Plans for Chronic 
Nonbacterial Osteomyelitis Refractory to Nonsteroidal Anti-Inflammatory Drugs and/or with 
Active Spinal Lesions. Arthritis Care Res (Hoboken) 2017;Nov 7:doi: 10.1002/acr.23462. [Epub 
ahead of print]. 
3. Wipff J, Costantino F, Lemelle I, Pajot C, Duquesne A, Lorrot M, et al. A large national cohort 
of French patients with chronic recurrent multifocal osteitis. Arthritis Rheumatol 
2015;67:1128–1137. 
4. Giedion A, Holthusen W, Masel LF VD. Subacute and chronic “symmetrical” osteomyelitis. 
Ann Radiol (Paris) 1972;15:329–42. 

 
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5. Beck C, Morbach H, Beer M, Stenzel M, Tappe D, Gattenlöhner S, et al. Chronic nonbacterial 
osteomyelitis in childhood: prospective follow-up during the first year of anti-inflammatory 
treatment. Arthritis Res Ther 2010;12:R74