Denosumab Treatment for Fibrous Dysplasia
Primary Purpose
Bone Diseases, Pain
Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Denosumab
Sponsored by
About this trial
This is an interventional treatment trial for Bone Diseases focused on measuring Bone Diseases, Fibrous Dysplasia (FD), Bone Turnover
Eligibility Criteria
INCLUSION CRITERIA:
- Age > or equal to 18 years
- Skeletal maturity with fusion of epiphyses documented radiographically
- Concomitant enrollment in the companion Screening and Natural History protocol 98-D-0145
- Confirmed diagnosis of Fibrous Dysplasia
- Self-reported FD-related bone pain at a site of FD, present for at least 3 months
- Ability to understand and provide informed consent
- Willing and able to complete the protocol scheduled assessments and medication regimen
- Willing and able to take calcium and vitamin D supplements provided by NIH
- Women of child bearing potential must use two forms of acceptable contraception: hormonal contraception (birth control pills, injected hormones or vaginal ring); intrauterine device and/or barrier methods (condom or diaphragm) used with spermicide. Surgical sterilization (hysterectomy, tubal ligation, or vasectomy in a partner) is considered one form of contraception therefore only one other form of contraception will be required in these subjects. Verbal confirmation will be obtained at screening that two forms of acceptable contraception are being used, and that the subjects agree to use the two forms of contraception from the time they sign study consent through five months after study completion (19 months total).
- Serum calcium or albumin-adjusted serum calcium within the normal range for the NIH laboratory.
EXCLUSION CRITERIA:
- Administration of denosumab within the previous year
- Use of bisphosphonates within one year prior to first day of the denosumab administration (Day 0). Examples of bisphosphonates include: pamidronate (Aredia), Alendronate (Fosamax) and Zoledronate (Zomata).
- Prior history, or current evidence, of osteomyelitis/osteonecrosis of the jaw or presence of an active dental or jaw condition which requires oral surgery
- Planned invasive dental procedure for the course of the study
- Presence of non-healed dental or oral surgery
- Orthopedic procedure performed less than 12-weeks prior to first day of the denosumab administration (Day 0)
- Acute fracture less than 12-weeks prior to first day of the denosumab administration (Day 0)
- 25-hydroxyvitamin D level than 30 ng/mL (patients will be eligible for re-screening after a repletion period lasting no longer than 6 months)
- Untreated or inadequately treated hypophosphatemia, defined as serum phosphate levels below the NIH normal range (patients will be eligible for re-screening after initiation or optimization of phosphorus replacement no longer than 6 months)
- Subject is pregnant or breast feeding, or planning to become pregnant or breastfeed while on study and through 5 months after completion of treatment
- Use of another investigational agent within the last 3 months prior to the first day of the denosumab administration (Day 0)
- Subject has known sensitivity to any of the products to be administered during the study (e.g. polyketide antibiotics, mammalian derived products, calcium, or vitamin D)
Sites / Locations
- National Institutes of Health Clinical Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
1
Arm Description
Denosumab will be administered at 120 mg per dose every 4 weeks for six months, with loading doses on days 8 and 15 of month 1.
Outcomes
Primary Outcome Measures
Primary:1. Assessment of markers of bone turnover: Beta-crosslaps, C-telopeptides (bone resorption marker,Procollagen-1-propeptide (bone formation marker)
Assessment of the effects of denosumab on: 1. Markers of bone turnover: Beta-crosslaps C-telopeptides (bone resorption marker) & Procollagen-1-propeptide (bone formation marker)
Secondary Outcome Measures
Secondary outcome #1- Bone histomorphometric indices: (SqrRoot) Mineralized perimeter, (SqrRoot) Bone formation rate (SqrRoot) Cortical width (SqrRoot) Cortical area (SqrRoot) Osteoid width...
Secondary endpoint #3 - Pain assessments utilizing the Brief Pain Inventory scores
Secondary Endpoint #2 - Surrogate markers of a direct therapeutic effect of denosumab on FD lesions:-Semi-quantitative changes in RANKL, Ki67 (marker of cell proliferation), p16 (marker od cell senescence), and/or apoptosis index-Sen...
Exploratory endpoint #3 - Effect measured by change in other outcome measures(SqrRoot) Bone density assessed by DXA(SqrRoot) Physical Medicine and Rehabilitation evaluation
Exploratory endpoint #2 - Denosumab discontinuation effect on:(SqrRoot) Biochemical markers of bone metabolism: beta-crosslaps C-telopeptides, procollagen-1 propeptide, bone specific alkaline phosphatase, osteocalcin, NTX-telopeptides
Exploratory Endpoint # 1. Effect of denosumab initiation and discontinuation on(SqrRoot) Serum calcium, phosphorus and parathyroid hormone (SqrRoot) Serum circulating RANKL and osteoprotegerin (OPG), and RANKL/OPG level...
Full Information
NCT ID
NCT03571191
First Posted
June 26, 2018
Last Updated
February 17, 2022
Sponsor
National Institute of Dental and Craniofacial Research (NIDCR)
1. Study Identification
Unique Protocol Identification Number
NCT03571191
Brief Title
Denosumab Treatment for Fibrous Dysplasia
Official Title
An Open Label Pilot Study of Denosumab Treatment for Fibrous Dysplasia
Study Type
Interventional
2. Study Status
Record Verification Date
February 15, 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
June 13, 2019 (Actual)
Primary Completion Date
November 17, 2021 (Actual)
Study Completion Date
March 15, 2030 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Dental and Craniofacial Research (NIDCR)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
Objectives:
The primary objective of this study is to evaluate the effect of denosumab on bone turnover in individuals with fibrous dysplasia (FD). Secondary objectives are to determine the effect of denosumab on bone pain, FD lesion intensity as revealed in 18F-sodium fluoride PET/CT bone scan, and to determine the effect of denosumab discontinuation on bone turnover re-bound after discontinuation.
Study Population:
Up to 14 adult subjects with FD may be enrolled to ensure complete study data on 9 subjects.
Design:
This study is a single center, open label pilot study of once-monthly dosing of denosumab. Subjects will be treated for 6 months, after which they will be followed by an 8-month observation period. A final visit will occur 21 months after denosumab discontinuation. Dosing will be adopted from studies in adults on treatment for giant cell tumors, with denosumab administered at 120 mg per dose every 4 weeks, with loading doses on days 7 and 14 of month 1.
Outcome Measures:
Primary:
Assessment of the effects of denosumab on:
1. Markers of bone turnover:
Beta-crosslaps C-telopeptides (bone resorption marker)
Procollagen-1-propeptide (bone formation marker)
Secondary:
Assessment of the effects of denosumab on:
Bone histomorphometric indices:
Mineralized perimeter
Bone formation rate
Cortical width
Cortical area
Osteoid width
Osteoid perimeter
Mineral apposition rate
Surrogate markers of a direct therapeutic effect of denosumab on FD lesions:
Semi-quantitative changes in RANKL, Ki67 (marker of cell proliferation), p16 (marker of cell senescence), and/or apoptosis index before and after treatment, as assessed by immunohistochemistry
Changes in sentinel lesion intensity, measured quantitatively by uptake on 18Fsodium fluoride PET/CT bone scan.
FD-related bone pain assessed by the Brief Pain Inventory (Short Form) , a validated self-reporting tool for assessment of pain.
Exploratory Endpoints:
Effect of denosumab initiation and discontinuation on
Serum calcium, phosphorus and parathyroid hormone
Serum RANKL and osteoprotegerin (OPG), and RANKL/OPG levels
Effect of denosumab discontinuation, as measured by the following outcomes:
Biochemical markers of bone metabolism: beta-crosslaps C-telopeptides, procollagen-1 propeptide, bone specific alkaline phosphatase, osteocalcin, NTX-telopeptides
Effect measured by change in other outcome measures, such as:
Bone density assessed by DXA
Physical Medicine and Rehabilitation evaluation
Detailed Description
Objectives:
The primary objective of this study is to evaluate the effect of denosumab on bone turnover in individuals with fibrous dysplasia (FD). Secondary objectives are to determine the effect of denosumab on bone pain, FD lesion intensity as revealed in 18F-sodium fluoride PET/CT bone scan, and to determine the effect of denosumab discontinuation on bone turnover re-bound after discontinuation.
Study Population:
Up to 14 adult subjects with FD may be enrolled to ensure complete study data on 9 subjects.
Design:
This study is a single center, open label pilot study of once-monthly dosing of denosumab. Subjects will be treated for 6 months, after which they will be followed by an 8-month observation period. A final visit will occur 21 months after denosumab discontinuation. Dosing will be adopted from studies in adults on treatment for giant cell tumors, with denosumab administered at 120 mg per dose every 4 weeks, with loading doses on days 7 and 14 of month 1.
Outcome Measures:
Primary:
Assessment of the effects of denosumab on:
1. Markers of bone turnover:
Beta-crosslaps C-telopeptides (bone resorption marker)
Procollagen-1-propeptide (bone formation marker)
Secondary:
Assessment of the effects of denosumab on:
Bone histomorphometric indices:
Mineralized perimeter
Bone formation rate
Cortical width
Cortical area
Osteoid width
Osteoid perimeter
Mineral apposition rate
Surrogate markers of a direct therapeutic effect of denosumab on FD lesions:
Semi-quantitative changes in RANKL, Ki67 (marker of cell proliferation), p16 (marker of cell senescence), and/or apoptosis index before and after treatment, as assessed by immunohistochemistry
Changes in sentinel lesion intensity, measured quantitatively by uptake on 18Fsodium fluoride PET/CT bone scan.
FD-related bone pain assessed by the Brief Pain Inventory (Short Form), a validated self-reporting tool for assessment of pain.
Exploratory Endpoints:
Effect of denosumab initiation and discontinuation on
Serum calcium, phosphorus and parathyroid hormone
Serum RANKL and osteoprotegerin (OPG), and RANKL/OPG levels
Effect of denosumab discontinuation, as measured by the following outcomes:
-Biochemical markers of bone metabolism: beta-crosslaps C-telopeptides, procollagen-1 propeptide, bone specific alkaline phosphatase, osteocalcin, NTX-telopeptides
Effect measured by change in other outcome measures, such as:
Bone density assessed by DXA
Physical Medicine and Rehabilitation evaluation
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bone Diseases, Pain
Keywords
Bone Diseases, Fibrous Dysplasia (FD), Bone Turnover
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
9 (Actual)
8. Arms, Groups, and Interventions
Arm Title
1
Arm Type
Experimental
Arm Description
Denosumab will be administered at 120 mg per dose every 4 weeks for six months, with loading doses on days 8 and 15 of month 1.
Intervention Type
Drug
Intervention Name(s)
Denosumab
Intervention Description
Denosumab will be administered at 120 mg per dose every 4 weeks for six months, with loading doses on days 8 and 15 of month 1.
Primary Outcome Measure Information:
Title
Primary:1. Assessment of markers of bone turnover: Beta-crosslaps, C-telopeptides (bone resorption marker,Procollagen-1-propeptide (bone formation marker)
Description
Assessment of the effects of denosumab on: 1. Markers of bone turnover: Beta-crosslaps C-telopeptides (bone resorption marker) & Procollagen-1-propeptide (bone formation marker)
Time Frame
every 3 months
Secondary Outcome Measure Information:
Title
Secondary outcome #1- Bone histomorphometric indices: (SqrRoot) Mineralized perimeter, (SqrRoot) Bone formation rate (SqrRoot) Cortical width (SqrRoot) Cortical area (SqrRoot) Osteoid width...
Time Frame
2 time points
Title
Secondary endpoint #3 - Pain assessments utilizing the Brief Pain Inventory scores
Time Frame
2 time points
Title
Secondary Endpoint #2 - Surrogate markers of a direct therapeutic effect of denosumab on FD lesions:-Semi-quantitative changes in RANKL, Ki67 (marker of cell proliferation), p16 (marker od cell senescence), and/or apoptosis index-Sen...
Time Frame
2-4 timepoints
Title
Exploratory endpoint #3 - Effect measured by change in other outcome measures(SqrRoot) Bone density assessed by DXA(SqrRoot) Physical Medicine and Rehabilitation evaluation
Time Frame
Q 3 mths/Q 6 mths
Title
Exploratory endpoint #2 - Denosumab discontinuation effect on:(SqrRoot) Biochemical markers of bone metabolism: beta-crosslaps C-telopeptides, procollagen-1 propeptide, bone specific alkaline phosphatase, osteocalcin, NTX-telopeptides
Time Frame
every 3 months
Title
Exploratory Endpoint # 1. Effect of denosumab initiation and discontinuation on(SqrRoot) Serum calcium, phosphorus and parathyroid hormone (SqrRoot) Serum circulating RANKL and osteoprotegerin (OPG), and RANKL/OPG level...
Time Frame
up to12 timepoints
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA:
Age > or equal to 18 years
Skeletal maturity with fusion of epiphyses documented radiographically
Concomitant enrollment in the companion Screening and Natural History protocol 98-D-0145
Confirmed diagnosis of Fibrous Dysplasia
Self-reported FD-related bone pain at a site of FD, present for at least 3 months
Ability to understand and provide informed consent
Willing and able to complete the protocol scheduled assessments and medication regimen
Willing and able to take calcium and vitamin D supplements provided by NIH
Women of child bearing potential must use two forms of acceptable contraception: hormonal contraception (birth control pills, injected hormones or vaginal ring); intrauterine device and/or barrier methods (condom or diaphragm) used with spermicide. Surgical sterilization (hysterectomy, tubal ligation, or vasectomy in a partner) is considered one form of contraception therefore only one other form of contraception will be required in these subjects. Verbal confirmation will be obtained at screening that two forms of acceptable contraception are being used, and that the subjects agree to use the two forms of contraception from the time they sign study consent through five months after study completion (19 months total).
Serum calcium or albumin-adjusted serum calcium within the normal range for the NIH laboratory.
EXCLUSION CRITERIA:
Administration of denosumab within the previous year
Use of bisphosphonates within one year prior to first day of the denosumab administration (Day 0). Examples of bisphosphonates include: pamidronate (Aredia), Alendronate (Fosamax) and Zoledronate (Zomata).
Prior history, or current evidence, of osteomyelitis/osteonecrosis of the jaw or presence of an active dental or jaw condition which requires oral surgery
Planned invasive dental procedure for the course of the study
Presence of non-healed dental or oral surgery
Orthopedic procedure performed less than 12-weeks prior to first day of the denosumab administration (Day 0)
Acute fracture less than 12-weeks prior to first day of the denosumab administration (Day 0)
25-hydroxyvitamin D level than 30 ng/mL (patients will be eligible for re-screening after a repletion period lasting no longer than 6 months)
Untreated or inadequately treated hypophosphatemia, defined as serum phosphate levels below the NIH normal range (patients will be eligible for re-screening after initiation or optimization of phosphorus replacement no longer than 6 months)
Subject is pregnant or breast feeding, or planning to become pregnant or breastfeed while on study and through 5 months after completion of treatment
Use of another investigational agent within the last 3 months prior to the first day of the denosumab administration (Day 0)
Subject has known sensitivity to any of the products to be administered during the study (e.g. polyketide antibiotics, mammalian derived products, calcium, or vitamin D)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alison M Boyce, M.D.
Organizational Affiliation
National Institute of Dental and Craniofacial Research (NIDCR)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
12. IPD Sharing Statement
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2018-D-0114.html
Description
NIH Clinical Center Detailed Web Page
Learn more about this trial
Denosumab Treatment for Fibrous Dysplasia
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