Denosumab for Glucocorticoid-treated Children With Rheumatic Disorders

Denosumab for Glucocorticoid-treated Children With Rheumatic Disorders: a Pilot Study

The purpose of this study is to evaluate denosumab as a novel treatment for bone loss in children treated with glucocorticoids for rheumatic disorders. This is a pilot Phase 1/2, randomized open-label, 12-month clinical trial of denosumab to assess its effect on bone resorption markers and bone mineral density (BMD) in children with rheumatic disorders, age 4 to 16 years, recruited within 1 month of starting a chronic systemic glucocorticoid regimen. Primary outcomes include suppression of bone turnover markers and safety assessments. Secondary outcomes include changes in bone density as measured by dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) densitometry at the radius and tibia.

Study Overview

• Status: Withdrawn
• Conditions: Vasculitis; Osteoporosis; Dermatomyositis; Juvenile Rheumatoid Arthritis; Glucocorticoid-induced Osteoporosis; Polyarthritis; Systemic Lupus Erythematosis
• Intervention / Treatment: Drug: denosumab

Detailed Description

The purpose of this study is to evaluate denosumab as a novel treatment for bone loss in children treated with glucocorticoids for rheumatic disorders. Children with rheumatic disorders are at risk for low bone density and fractures from the inflammatory effects of the underlying disease, and also from direct effects of glucocorticoids on bone. This is a pilot Phase 1/2, randomized open-label, 12-month clinical trial of denosumab to assess its effect on bone resorption markers and BMD in children with rheumatic disorders, age 4 to 16 years, recruited within 1 month of starting a chronic systemic glucocorticoid regimen. Two different sequential doses will be administered to the intervention group and evaluation for safety and efficacy will be conducted at study visits. Primary outcomes include suppression of bone turnover markers and safety assessments. Secondary outcomes include changes in bone density as measured by dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) densitometry at the radius and tibia.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 16 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 4 to 16 years of age.
2. Diagnosis of one of the following by a rheumatologist using standard criteria: juvenile dermatomyositis, juvenile idiopathic arthritis, systemic arthritis, seronegative or seropositive polyarthritis, psoriatic arthritis, systemic lupus or systemic vasculitis.
3. Within 1 month of initiating glucocorticoids ≥0.5 mg/kg prednisone equivalent daily, planned for ≥ 6 months.
4. BMD by DXA with Z-score < 0.0 on screening at lumbar spine or total body less head (TBLH).

Exclusion Criteria:

1. Previous treatment with a bisphosphonate, or other osteoporosis medication.
2. Metabolic bone disorders besides glucocorticoid-induced osteoporosis; other disorders treated with systemic glucocorticoids (inflammatory bowel disease, severe pulmonary disease, nephrotic syndrome, etc.).
3. Intent to treat with a tumor necrosis factor inhibitor or Interleukin 6 receptor antagonist during the first 6 months.
4. Glomerular filtration rate < 30ml/min [pediatric estimated glomerular filtration rate = 0.413*(height/serum creatinine)] 75
5. Planned orthopedic or other major surgery during the course of the study (at the time of enrollment)
6. Significant dental caries, or plans to undergo invasive oral procedures during the subsequent 12 months.
7. Known allergy to latex (drug packaging includes a natural rubber stopper), fructose intolerance or other denosumab contraindication.
8. 25-hydroxyvitamin D (25OHD) level < 32 ng/dl. Subjects with 25OHD <32 ng/ml may be given cholecalciferol and rescreened.
9. Hypocalcemia at screening (total serum calcium < 8.5 mg/dl after correction for albumin level).
10. Chronic ventilator dependence, or other conditions increasing risk of participation.
11. Pregnancy, or refusal to use acceptable contraception or abstain during the protocol (post-pubertal female).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Denosumab; These subjects will receive two sequential doses of denosumab	Drug: denosumab; These subjects will receive two doses of denosumab.; Other Names: Prolia
No Intervention: No drug intervention; These subjects do not receive denosumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Changes in bone turnover marker (N-telopeptide (NTX) /creatinine ratio).	2 weeks, 1 month, 2 month, 3 month after each dose day.

Secondary Outcome Measures

Outcome Measure	Time Frame
The duration of suppression of the NTX/creatinine ratio	up to six months after each dose day
The changes in bone specific alkaline phosphorus	From baseline to 1 week, 1,3,6 months after each dose day
Changes of BMD spine Z-scores	12 month
Changes of BMD Total body less head (TBLH) Z-scores	12 month
Changes of volumetric BMD on peripheral quantitative computed tomography	12 month
Changes of polar strength-strain index at tibia	12 month
Changes of polar strength-strain index at radius	12 month
Changes in bone strength index for compression at tibia.	12 month
Changes in bone strength index for compression at radius	12 month
The relationships of Interleukin 6 to baseline NTX/creatinine ratio	baseline visit
The relationships of Interleukin 6 to baseline DXA	baseline visit
The relationships of Interleukin 6 to baseline pQCT variables.	baseline visit
The relationships of receptor activator of nuclear factor-kappa B ligand (RANKL) to baseline NTX/creatinine ratio	baseline visit
The relationships of receptor activator of nuclear factor-kappa B ligand (RANKL) to baseline BMD	baseline visit
The relationships of receptor activator of nuclear factor-kappa B ligand (RANKL) to baseline volumetric BMD	baseline visit
Dose limiting toxicities (DLTs), including hypocalcemia	3 days, 1 week, 2, week, month 3,4,5,6 after each dose; or any other visits.

Collaborators and Investigators

• Sponsor: Indiana University
• Investigators: Principal Investigator: Erik Imel, MD, Indiana University

Study record dates

Study Major Dates

• Study Start (Anticipated): August 1, 2019
• Primary Completion (Anticipated): June 1, 2021
• Study Completion (Anticipated): June 1, 2021

Study Registration Dates

• First Submitted: April 6, 2015
• First Submitted That Met QC Criteria: April 13, 2015
• First Posted (Estimate): April 16, 2015

Study Record Updates

• Last Update Posted (Actual): December 6, 2019
• Last Update Submitted That Met QC Criteria: December 4, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: pediatric; osteoporosis; glucocorticoid; rheumatology; denosumab
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Nervous System Diseases; Skin Diseases; Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Muscular Diseases; Neuromuscular Diseases; Bone Diseases; Bone Diseases, Metabolic; Polymyositis; Myositis; Arthritis; Lupus Erythematosus, Systemic; Osteoporosis; Dermatomyositis; Arthritis, Juvenile; Vasculitis; Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: 1504269855

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No