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Clinical Trial 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:

1. Bone histomorphometric indices:

Mineralized perimeter

Bone formation rate

Cortical width

Cortical area

Osteoid width

Osteoid perimeter

Mineral apposition rate

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 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.

3. FD-related bone pain assessed by the Brief Pain Inventory (Short Form) , a validated self-reporting tool for assessment of pain.

Exploratory Endpoints:

1. Effect of denosumab initiation and discontinuation on

Serum calcium, phosphorus and parathyroid hormone

Serum RANKL and osteoprotegerin (OPG), and RANKL/OPG levels

2. 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

3. Effect measured by change in other outcome measures, such as:

Bone density assessed by DXA

Physical Medicine and Rehabilitation evaluation


Clinical Trial 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:

1. Bone histomorphometric indices:

- Mineralized perimeter

- Bone formation rate

- Cortical width

- Cortical area

- Osteoid width

- Osteoid perimeter

- Mineral apposition rate

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 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.

3. FD-related bone pain assessed by the Brief Pain Inventory (Short Form), a validated self-reporting tool for assessment of pain.

Exploratory Endpoints:

1. Effect of denosumab initiation and discontinuation on

- Serum calcium, phosphorus and parathyroid hormone

- Serum RANKL and osteoprotegerin (OPG), and RANKL/OPG levels

2. 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

3. Effect measured by change in other outcome measures, such as:

- Bone density assessed by DXA

- Physical Medicine and Rehabilitation evaluation ;


Study Design


Related Conditions & MeSH terms


NCT number NCT03571191
Study type Interventional
Source National Institutes of Health Clinical Center (CC)
Contact
Status Enrolling by invitation
Phase Phase 2
Start date September 19, 2018
Completion date January 31, 2019

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