Study of Denosumab for Prevention of Skeletal Disease Progression in Children With Fibrous Dysplasia

• ClinicalTrials.gov Identifier: NCT05419050
• Recruitment Status: Recruiting
• First Posted: June 15, 2022
• Last Update Posted: April 2, 2024
• Sponsor: National Institute of Dental and Craniofacial Research (NIDCR)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Dental and Craniofacial Research (NIDCR) )

Study Description

Brief Summary:

Background:

Fibrous dysplasia (FD) is a disease that affects the bones. It causes bone lesions that can become weak and lead to fractures, deformity, and nerve injuries. FD bone lesions begin to develop soon after birth and grow during childhood. The lesions stop growing in adults but can still cause disability. Researchers want to find ways to stop the growth of FD bone lesions.

Objective:

To test a study drug (denosumab) in children with FD.

Eligibility:

Children aged 4 to 14 years with FD and who are also enrolled in the Screening and Natural History protocol (98-D-0145).

Design:

Participants will have a screening visit at the NIH clinic or by telehealth. Their medical history will be reviewed.

Participants will stay overnight in the hospital 4 times in 76 weeks. Each stay will last 5 to 7 nights.

Participants will also visit a local lab for blood and urine tests every 4 weeks during the study.

Participants will receive denosumab once every 4 weeks for 48 weeks. The medication is given as a shot injected under the skin using a small needle. Some injections may be performed at home by a caregiver. The caregiver will receive training for this procedure.

Participants will undergo many tests that may be repeated throughout the study. They will have a dental exam. They will have tests of their strength and ability to move freely. They will have x-rays and other scans to get pictures of their bones.

Participants will be given another medicine that is administered through a needle in the arm over 30 minutes.

Condition or disease	Intervention/treatment	Phase
Fibrous Dysplasia	Drug: denosumab	Phase 2

Detailed Description:

Study Description:

This will be a phase 2, open label, single arm study of denosumab treatment to prevent fibrous dysplasia (FD) lesion progression in children.

Objectives:

Primary Objective:

Evaluate the effect of denosumab on FD lesion progression in children.

Secondary Objectives:

• Evaluate the effects of denosumab on FD lesion activity.
• Evaluate the effect of denosumab on strength and mobility.
• Evaluate the effect of denosumab on pain and quality of life.
• Evaluate the safety and tolerability of denosumab in children with FD.

Endpoints:

Primary Endpoint:

Change in Skeletal Burden Score from baseline to 48 weeks

Secondary Endpoints:

• Percent change in serum bone turnover markers from baseline to 48 weeks: Procollagen 1 Intact N-Terminal Propeptide (P1NP, formation marker), C- telopeptides (CTX, resorption marker), osteocalcin, and bone-specific alkaline phosphatase
• Change in 18F-NaF PET/CT total lesion activity from baseline to 48 weeks
• Change in 18F-NaF PET/CT sentinel lesion intensity (SUVmax) from baseline to 48 weeks
• Change in functional parameters from baseline to 48 weeks, including muscle strength, range-of-motion, and walking speed
• Change in patient-reported outcome scales evaluating pain and quality of life from baseline to 48 weeks, including PROMIS Pediatric measures of Pain Intensity, Pain Interference, Mobility, and Fatigue.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Denosumab for Prevention of Skeletal Disease Progression in Children With Fibrous Dysplasia
• Actual Study Start Date: October 12, 2022
• Estimated Primary Completion Date: June 1, 2024
• Estimated Study Completion Date: June 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: treatment; treatment arm	Drug: denosumab; monoclonal antibody to receptor activator of nuclear kappa-B ligand (RANKL), a protein involved in regulating osteoclastogenesis

Outcome Measures

Primary Outcome Measures :

1. Change in Skeletal Burden Score [ Time Frame: 48 weeks ]
   Skeletal Burden Score is a validated measure for quantifying FD disease burden shown to correlate with skeletal outcomes

Secondary Outcome Measures :

1. Percent change in serum bone turnover markers from baseline to 48 weeks: procollagen 1 propeptide (P1NP, formation marker), beta crosslaps telopeptides (CTX, resorption marker), osteocalcin, and bone-specific alkaline phosphatase [ Time Frame: 48 weeks ]
   reflect underlying bone turnover, and correlate with skeletal outcomes
2. Adverse events [ Time Frame: 76 weeks ]
   Safety endpoints for expected and unexpected adverse events
3. Change in functional parameters: - Muscle strength - Range-of-motion - Walking speed (6-minute walk) [ Time Frame: 48 weeks ]
   Outcome measures that reflect activities of daily living
4. Change in 18F-NaF PET/CT total lesion activity from baseline to 48 weeks [ Time Frame: 48 weeks ]
   reflect underlying lesion activity and correlate with skeletal outcomes
5. Change in patient-reported outcome scales: - SF10 - Brief Pain Inventory - Brief Fatigue Inventory [ Time Frame: 48 weeks ]
   Outcome measures to determine pain and quality of life
6. Change in 18F-NaF PET/CT sentinel lesion intensity (SUVmax) [ Time Frame: 48 weeks ]
   reflect underlying lesion activity and correlate with skeletal outcomes

Eligibility Criteria

• Ages Eligible for Study: 4 Years to 14 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Confirmed diagnosis of fibrous dysplasia
• Age 4 to 14 years
• Concurrent enrollment in the companion Screening and Natural History protocol 98-D-0145
• Provision of signed and dated informed consent form
• Stated willingness of guardian/Legally Authorized Representative (LAR) to comply with all study procedures and availability for the duration of the study
• Ability of guardian/LAR to understand and the willingness to sign a written informed consent document

• For females of reproductive potential: agreement to use highly effective contraception for during study participation. Highly effective contraception methods include:

  • Total abstinence. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

  • Combination of the following (a+b or a+c, or b+c):

    • Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception
    • Placement of an intrauterine device (IUD) or intrauterine system (IUS)
    • Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
• For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner
• Minimum body weight of 12 kilograms

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

• Pregnancy or lactation
• Known allergic reactions to denosumab
• Prior history, or current evidence, of osteomyelitis/osteonecrosis of the jaw
• Planned invasive dental procedure for the course of the study
• Presence of non-healed dental or oral surgery
• Orthopedic procedure performed less than 6-weeks prior to first day of the denosumab administration (Day 0)
• Acute fracture less than 6-weeks prior to first day of the denosumab administration (Day 0)
• Serum calcium or albumin-adjusted serum calcium below the normal range for the NIH laboratory (patients will be eligible for re-screening after a repletion period lasting up to 6 months)
• 25-hydroxyvitamin D level than 20 ng/mL (patients will be eligible for re screening after a repletion period lasting up to 6 months)
• Untreated or inadequately treated hypophosphatemia as determined by the principal investigator (patients will be eligible for re-screening after initiation or optimization of phosphorus replacement no longer than 6 months)
• Inability to comply with a non-sedated 18F-NaF PET/CT (subjects will be eligible for re- screening after 6 months)
• Use of another investigational agent within the last 3 months prior to the first day of the denosumab administration (Day 0)
• Have any condition which in the opinion of the PI could present a concern for subject safety or difficulty with data interpretation.

Contacts and Locations

Contacts

Contact: Alison M Boyce, M.D.; (301) 827-4802; alison.boyce@nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY dial 711 ccopr@nih.gov

Sponsors and Collaborators

National Institute of Dental and Craniofacial Research (NIDCR)

Investigators

• Principal Investigator: Alison M Boyce, M.D.; National Institute of Dental and Craniofacial Research (NIDCR)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

• Responsible Party: National Institute of Dental and Craniofacial Research (NIDCR)
• ClinicalTrials.gov Identifier: NCT05419050
• Other Study ID Numbers: 10000780; 000780-D
• First Posted: June 15, 2022
• Last Update Posted: April 2, 2024
• Last Verified: March 29, 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: .all IPD that underlie results in a publication
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: starting 6 months after publication
• Access Criteria: Data will be shared on reasonable request to the PI

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Dental and Craniofacial Research (NIDCR) ):

McCune-Albright Syndrome

Additional relevant MeSH terms:

Fibrous Dysplasia of Bone; Disease Progression; Pathologic Processes; Disease Attributes; Osteochondrodysplasias; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Denosumab; Bone Density Conservation Agents; Physiological Effects of Drugs