1 Year Open-label Extension to CZOL446H2337 Safety and Efficacy Trial of Zoledronic Acid Twice Yearly in Osteoporotic Children Treated With Glucocorticoids

Study Overview
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Brief Summary
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This 1-year open-label extension to CZOL446H2337 is designed to evaluate the safety and efficacy of zoledronic acid twice yearly in osteoporotic children treated with glucocorticoids.

Official Title
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A 1-year, Multicenter, Open-label Extension to CZOL446H2337 to Evaluate Safety and Efficacy of Zoledronic Acid Twice Yearly in Osteoporotic Children Treated With Glucocorticoids

Conditions
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Osteoporosis

Intervention / Treatment
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* Drug: Zoledronic acid


Participation Criteria
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Eligibility Criteria
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Key Inclusion criteria: Written informed consent before any study-related procedure. Group 1: Children and adolescents, male or female, 6-19 years old, who met the inclusion criteria for entry into the Core study and who took at least one dose of study drug and have completed Visit 8 of the CZOL446H2337 Core study. Patient must be enrolled into the extension at Visit 9 up to 10 months after Visit 5 (month 6) of the Core study. Patients who followed the regimen of calcium and vitamin D intake as required in the Core study through diet or supplementation. Group 2: Children and adolescents, male or female, 5 - 17 years old who met the inclusion criteria for entry into the Core study but were not enrolled because of clinically significant back pain from vertebral fracture and the preexisting clinical care at the Investigator site is to treat this type of patient with a bisphosphonate. Confirmed diagnosis of non-malignant conditions (including but not limited to rheumatic conditions, inflammatory bowel disease, Duchenne muscular dystrophy, nephrotic syndrome), treated with systemic glucocorticoids (i.v. or oral) within the 12 months preceding enrollment in the study (any duration) LS-BMD Z-score of -0.5 or worse confirmed by the central imaging vendor Evidence of at least 1 vertebral compression fracture (at least Genant Grade 1 vertebral compression or radiographic signs of vertebral compression) confirmed by central reading OR At least one lower OR 2 upper extremity long-bone, low-trauma, fracture which occurred sometime within the 2 years or preceding enrollment in the study, confirmed by radiological report. (*Low trauma fracture is defined as falling from standing height or less). Key Exclusion criteria: Major protocol violation in the Core Study (Group 1 only). Prior use of bisphosphonates (Group 2 only) or sodium fluoride (doses for osteoporosis not for dental hygiene). Hypocalcemia and hypophosphatemia: any value (age-matched) below the normal range at Visit 8 or 8A. Vitamin D deficiency (serum 25-hydroxy vitamin D concentrations of < 20 ng/mL or < 50 nmol/L) at Visit 8 (Group 1) or Visit 8A (Group 2). Renal impairment defined as an estimated glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 at screening based on the Schwartz formula at Visit 8 or 8 A; a serum creatinine above the normal range at Visit 9 (Group 1) or an increase between Visit 8A and Visit 9 greater than 0.5 mg/dL (44.2 μmol/L) for Group 2. Female patients of child bearing potential are eligible only if they are not pregnant/non-lactating. Females of child bearing potential must be practicing a medically acceptable form of birth control for greater than 2 months prior to screening visit and consent to pregnancy tests during the study.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zoledronic acid<br>Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid | Drug: Zoledronic acid<br>* intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Long-term 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 given long-term, over an additional 12 months from the Core study (CZOL446H2337), is safe for the treatment of osteoporotic children treated with glucocorticoids through the monitoring of relevant clinical and laboratory safety parameters. | Baseline 1 (Visit 1 of the Core Study) through Month 24 (Visit 15/Final Extension Visit) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline 1 (Visit 1 of the Core Study) in Lumbar Spine Bone Mineral Density (BMD) Z-score at Month 18 and 24 by Core Treatment Group. | Lumbar Spine Bone Mineral Density (BMD) Z-score was determined by the central imaging vendor at the final visit of Core study (Visit 8) or at 1st infusion visit (Visit 9), and thereafter at Visit 12 (Month 18) and Visit 15 (Month 24) (final Extension Study visit/EOS) of Extension study. 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 Core baseline indicated an improvement in condition. | Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit) | 
| Mean Change From Baseline 1 (Visit 1 of the Core Study) in Lumbar Spine Bone Mineral Content (BMC) at Month 18 and 24 by Core Treatment Group. | Lumbar Spine Bone Mineral Content (BMC) was determined by the central imaging vendor at the final visit of Core study (Visit 8) or at 1st infusion visit (Visit 9), and thereafter at Visit 12 (Month 18) and Visit 15 (Month 24) (final Extension Study visit/EOS) of Extension study. The methods to be used to measure BMC were described in the respective DXA Manuals. Positive changes from Core baseline indicated an improvement in condition. | Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit) | 
| Mean Change From Baseline 1 (Visit 1 of the Core Study) in Total Body BMC at Month 18 and 24 by Core Treatment Group. | Total body BMC were determined by the central imaging vendor at the final visit of Core study (Visit 8) or at 1st infusion visit (Visit 9), and thereafter at Visit 12 (Month 18) and Visit 15 (Month 24) (final Extension Study visit/EOS) of Extension study. The methods to be used to measure BMC were described in the respective DXA Manuals. Positive changes from Core baseline indicated an improvement in condition. | Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit) | 
| Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum P1NP at Month 18 and 24 by Core Treatment Group. | Serum Procollagen type 1 amino-terminal propeptide (P1NP) was collected at the final visit Core study at Visit 8, or at 1st infusion visit (Visit 9), and thereafter at Visit 12 (Month 18) and Visit 15 (Month 24) (final Extension study Visit/EOS) of Extension study according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory. Decrease or negative changes from Core baseline indicated a pharmacological response to therapy. | Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit) | 
| Mean Change From Baseline 1 (Visit 1 of the Core Study) in BSAP at Month 18 and 24 by Core Treatment Group. | Bone specific alkaline phosphatase (BSAP) was collected at the final visit Core study at Visit 8, or at 1st infusion visit (Visit 9), and thereafter at Visit 12 (Month 18) and Visit 15 (Month 24) (final Extension study Visit/EOS) of Extension study according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory. Decrease or negative changes from Core baseline indicated a pharmacological response to therapy. | Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit) | 
| Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum NTX at Month 18 and 24 by Core Treatment Group. | Serum Cross linked N-telopeptide (NTX) was collected at the final visit Core study at Visit 8, or at 1st infusion visit (Visit 9), and thereafter at Visit 12 (Month 18) and Visit 15 (Month 24) (final Extension study Visit/EOS) of Extension study according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory. Decrease or negative changes from Core baseline indicated a pharmacological response to therapy. | Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit) | 
| Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum TRAP-5b at Month 18 and 24 by Core Treatment Group. | Serum Tartrate-resistant acid phosphatase isoform 5b (TRAP 5b) were collected at the final visit Core study at Visit 8, or at 1st infusion visit (Visit 9), and thereafter at Visit 12 (Month 18) and Visit 15 (Month 24) (final Extension study Visit/EOS) of Extension study according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory. Decrease or negative changes from Core baseline indicated a pharmacological response to therapy. Decrease or negative changes from Core baseline indicated a pharmacological response to therapy. | Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit) | 
| Number of Participants With New Vertebral Fractures During the 12 Month Extension Period by Core Treatment Group. | New vertebral fractures are defined as fractures of Genant grade 1 or higher that occur at lumbar or thoracic spine from first extension dose infusion to the end of the study in a previously normal vertebra. | Month 24 (Visit 15/Final Extension Visit) | 
| Number of Participants With New Morphometric Vertebral Fractures During the 12 Month Extension Period by Core Treatment Group. | 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. A new morphometric vertebral fractures during the 12 month Extension Period was defined as a morphometric vertebral fracture present at Month 24 X-ray which was not present at the Extension Baseline (Baseline 2). | Month 24 (Visit 15/Final Extension Visit) | 
| Percentage of Patients With Reduction in Pain From Baseline 1 (Visit 1 of the Core Study) at Month 15, 18, 21 and 24 by Core Treatment Group. | Pain was evaluated at each visit (at office and telephone visit) at the final visit of the Core study and first visit of the Extension study (Visit 9), Visits 11 (Month 15), 12 (Month 18), 14 (Month 21) and 15 (Month 24) 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 Core 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 15, Month 18, Month 21, Month 24 | 
| Mean Change From Baseline (Core and Extension) in 2nd Metacarpal Cortical Width at Month 24 by Core Treatment Group. | Left postero-anterior (PA) hand/wrist X-ray were taken at the final visit of Core study and at Visit 15/EOS (Month 24) to assess bone age. The change in 2nd metacarpal cortical width at Month 24 relative to the respective Baseline was calculated. If a fracture of the left upper extremity precluded radiographic imaging, (or precluded this X-ray in the Core study) then the right hand was evaluated for this purpose. In this case, an image of the right hand was carried out at both Visit 8 and at Visit 15/EOS (Month 24). The information was used in the assessment of bone density. | Baseline 1 (Visit 1 of the Core Study) and Baseline 2 (Visit 9 of the Extension Study) through Month 24 (Visit 15/Final Extension Visit) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteoporosis, children and adolescents, zoledronic acid, chronic inflammation, Duchenne muscular dystrophy, glucocorticoids, chronic inflammatory conditions