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) )

Tracking Information

• First Submitted Date: June 11, 2022
• First Posted Date: June 15, 2022
• Last Update Posted Date: April 2, 2024
• Actual Study Start Date: October 12, 2022
• Estimated Primary Completion Date: June 1, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 14, 2022)

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 14, 2022)

• 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
• Adverse events [ Time Frame: 76 weeks ]
  Safety endpoints for expected and unexpected adverse events
• 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
• 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
• 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
• Change in 18F-NaF PET/CT sentinel lesion intensity (SUVmax) [ Time Frame: 48 weeks ]
  reflect underlying lesion activity and correlate with skeletal outcomes

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Denosumab for Prevention of Skeletal Disease Progression in Children With Fibrous Dysplasia
• Official Title: A Phase 2 Study of Denosumab for Prevention of Skeletal Disease Progression in Children With Fibrous Dysplasia

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.

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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Fibrous Dysplasia

Intervention

Drug: denosumab

monoclonal antibody to receptor activator of nuclear kappa-B ligand (RANKL), a protein involved in regulating osteoclastogenesis

Study Arms

Experimental: treatment

treatment arm

Intervention: Drug: denosumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 14, 2022): 15
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 1, 2024
• Estimated Primary Completion Date: June 1, 2024 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 4 Years to 14 Years (Child)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05419050
• Other Study ID Numbers: 10000780; 000780-D
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

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

IPD Sharing Statement

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

• Current Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Dental and Craniofacial Research (NIDCR) )
• Original Responsible Party: Same as current
• Current Study Sponsor: National Institute of Dental and Craniofacial Research (NIDCR)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: March 29, 2024