An Efficacy and Safety Trial of Intravenous Zoledronic Acid Twice Yearly in Osteoporotic Children Treated With Glucocorticoids

A Multicenter, Randomized, Double-blind, Placebo Controlled Efficacy and Safety Trial of Intravenous Zoledronic Acid Twice Yearly Compared to Placebo in Osteoporotic Children Treated With Glucocorticoids.

This study was designed to evaluate the efficacy and safety of zoledronic acid compared to placebo in osteoporotic children treated with glucocorticoids

Study Overview

• Status: Completed
• Conditions: Osteoporosis
• Intervention / Treatment: Drug: Placebo; Drug: Zoledronic acid

Detailed Description

In March 2017, Novartis stopped enrollment as the study was not feasible to be conducted due to low enrollment and other recruitment challenges. Patients receiving the treatment continued to receive the treatment per protocol.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Novartis Investigative Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • Novartis Investigative Site
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0Z2
      • Novartis Investigative Site
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L1
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Novartis Investigative Site
    • Montreal, Quebec, Canada, H3H 1P3
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1085
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 119991
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 195067
    • Novartis Investigative Site
• South Africa
  • Gauteng
    • Soweto, Gauteng, South Africa, 2013
      • Novartis Investigative Site
• United Kingdom
  • Manchester, United Kingdom, M14 0JH
    • Novartis Investigative Site
  • Birmingham
    • West Midlands, Birmingham, United Kingdom, B4 6NH
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• A diagnosis of chronic rheumatologic conditions or inflammatory bowel disease or Duchenne muscular dystrophy requiring systemic glucocorticoids (i.v. or oral) within 12 months prior to screening
• Lumbar Spine BMDZ-score of -0.5 or worse
• Evidence of at least at least 1 vertebral compression fracture of Genant Grade 1 or higher (or radiographic signs of vertebral fracture) within 1 month from Screening visit OR One or more, low-trauma, lower extremity long-bone fracture which occurred sometime within the 2 years PRECEDING enrollment in the study OR Two or more, low-trauma, upper extremity long-bone fractures which occurred sometime within the 2 years PRECEDING enrollment in the study
• Consent/assent to study participation

Key Exclusion Criteria:

• History of primary bone disease (OI, Idiopathic Juvenile Osteoporosis, Rickets/Osteomalacia)
• Any medical condition that might have interfered with the evaluation of lumbar spine BMD, such as severe scoliosis or spinal fusion. Patients with less than 3 evaluable vertebrae by Dual Energy X-ray Absorptiometry (DXA) evaluation in the region of interest lumbar 1 (L1) to lumbar 4 (L4),
• Hypocalcemia and hypophosphatemia
• Serum 25-hydroxy vitamin D concentrations of <20 ng/mL or <50 nmol/L
• estimated glomerular filtration rate (GFR) <60 mL/min/1.73 m2
• serum creatinine increase between Visit 1 and Visit 2 >0.5 mg/dL (44.2 μmol/L)
• Uncontrolled symptoms of cardiac failure or arrhythmia
• Any prior use of bisphosphonates, or high dose sodium fluoride

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zoledronic acid; Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid	Drug: Zoledronic acid; intravenous infusion
Placebo Comparator: Placebo; Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Drug: Placebo; intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score at Month 12	Lumbar Spine Bone Mineral Density (BMD) Z-score was determined by the central imaging vendor before first treatment and at Month 12. The methods to be used to measure Lumbar Spine BMD Z-score were described in the respective DXA Manuals provided by central imaging vendor. Positive changes from baseline indicated an improvement in condition.	Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score at Month 6	Lumbar Spine Bone Mineral Density (BMD) Z-score was determined by the central imaging vendor before first treatment and at Month 6. The methods to be used to measure Lumbar Spine BMD Z-score were described in the respective DXA Manuals provided by central imaging vendor. Positive changes from baseline indicated an improvement in condition.	Month 6
Mean Change From Baseline in Lumbar Spine BMC at Month 6 and 12	Lumbar Spine BMC was determined by the central imaging vendor before first treatment and at Months 6 and 12. The methods to be used to measure BMC were described in the respective DXA Manuals.	Month 6, Month 12
Mean Change From Baseline in Total Body BMC at Month 6 and 12	Total body BMC was all determined by the central imaging vendor before first treatment and at Months 6 and 12. The methods to be used to measure BMC were described in the respective DXA Manuals.	Month 6, Month 12
Mean Change From Baseline in Serum P1NP at Months 6 and 12	Serum Procollagen type 1 amino-terminal propeptide (P1NP) was collected before first treatment (baseline) and at Months 6 and Month 12 according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory.	Month 6, Month 12
Mean Change From Baseline in BSAP at Months 6 and 12	Bone specific alkaline phosphatase (BSAP) were collected before first treatment (baseline) and at Months 6 and Month 12 according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory.	Month 6, Month 12
Mean Change From Baseline in Serum NTX at Months 6 and 12	Serum Cross linked N-telopeptide (NTX) were collected before first treatment (baseline) and at Months 6 and Month 12 according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory.	Month 6, Month 12
Mean Change From Baseline in Serum TRAP-5b at Months 6 and 12	Serum Tartrate-resistant acid phosphatase isoform 5b (TRAP 5b) was collected before first treatment (baseline) and at Months 6 and Month 12 according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory.	Month 6, Month 12
Number of Participants With New Vertebral Fractures at Month 12	New vertebral fractures were defined as fractures of Genant Grade 1 or higher that occurred at lumbar or thoracic spine from first dose infusion to the end of the study.	Month 12
Mean Change From Baseline in Vertebral Morphometry at Month 12	Vertebral morphometry (or concave index) was calculated using the average ratio between mid-height and posterior height from L1 to L4 and performed by a central reader.	Month 12
Percentage of Patients With Reduction in Pain at Months 3, 6, 9 and 12	Pain was evaluated at each visit (in office and telephone visit) at randomization, Months 3, 6, 9 and 12 using the Faces Pain Scale-Revised (FPS-R). Children were selecting the face that best fits their pain. The pain score ranged from 0 (No Pain) to 10 (Very Much Pain). The reduction in pain from baseline by visit was evaluated based on whether or not patients had a decrease in their FPS-R from baseline. If pain remained the same or worsened from baseline a patient was classified as '0' and if the pain scale decreased then the patient was classified as '1'.	Month 3, Month 6, Month 9 and Month 12
Mean Change From Baseline in 2nd Metacarpal Cortical Width at Month 12	Left posteroanterior (PA) hand/wrist X-ray were taken at Visit 1 and at the Month 12 visit to assess bone age and the between-treatment differences for change in 2nd metacarpal cortical width at Month 12 relative to baseline. If a fracture of the left upper extremity precluded radiographic imaging, then the right hand was evaluated for this purpose. In this case, the right hand was be imaged at both Visit 1 and at Month 12. The information was used in the assessment of bone density.	Month 12
Urinary Concentration of Zoledronic Acid at Month 12	Urine was collected overnight or for at least 4 waking hours from all patients able to provide specimens, to measure urinary concentration of zoledronic acid at Month 12. Only descriptive analysis done.	Month 12
Safety of Zoledronic Acid for the Treatment of Osteoporotic Children Treated With Glucocorticoids	Analysis of absolute and relative frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) to demonstrate that zoledronic acid is safe for the treatment of osteoporotic children treated with glucocorticoids through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis done.	Baseline through Month 12

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Ward LM, Choudhury A, Alos N, Cabral DA, Rodd C, Sbrocchi AM, Taback S, Padidela R, Shaw NJ, Hosszu E, Kostik M, Alexeeva E, Thandrayen K, Shenouda N, Jaremko JL, Sunkara G, Sayyed S, Aftring RP, Munns CF. Zoledronic Acid vs Placebo in Pediatric Glucocorticoid-induced Osteoporosis: A Randomized, Double-blind, Phase 3 Trial. J Clin Endocrinol Metab. 2021 Nov 19;106(12):e5222-e5235. doi: 10.1210/clinem/dgab458.

Study record dates

Study Major Dates

• Study Start (Actual): December 4, 2008
• Primary Completion (Actual): March 5, 2018
• Study Completion (Actual): March 5, 2018

Study Registration Dates

• First Submitted: November 26, 2008
• First Submitted That Met QC Criteria: November 26, 2008
• First Posted (Estimate): November 27, 2008

Study Record Updates

• Last Update Posted (Actual): September 2, 2020
• Last Update Submitted That Met QC Criteria: September 1, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Osteoporosis, children and adolescents, zoledronic acid, chronic inflammation, Duchenne muscular dystrophy, glucocorticoids, chronic inflammatory conditions
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis; Physiological Effects of Drugs; Bone Density Conservation Agents; Zoledronic Acid
• Other Study ID Numbers: CZOL446H2337; 2008-001252-52 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.