Osteoporosis
Conditions
Keywords
Osteoporosis, children and adolescents, zoledronic acid, chronic inflammation, Duchenne muscular dystrophy, glucocorticoids, chronic inflammatory conditions
Brief summary
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.
Interventions
DRUGZoledronic acid
intravenous infusion
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 19 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion criteria: Written informed consent before any study-related procedure. Group 1: 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. 2. Patient must be enrolled into the extension at Visit 9 up to 10 months after Visit 5 (month 6) of the Core study. 3. Patients who followed the regimen of calcium and vitamin D intake as required in the Core study through diet or supplementation. Group 2: 1. 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. 2. 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) 3. LS-BMD Z-score of -0.5 or worse confirmed by the central imaging vendor 4. 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
1. Major protocol violation in the Core Study (Group 1 only). 2. Prior use of bisphosphonates (Group 2 only) or sodium fluoride (doses for osteoporosis not for dental hygiene). 3. Hypocalcemia and hypophosphatemia: any value (age-matched) below the normal range at Visit 8 or 8A. 4. 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). 5. 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. 6. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Long-term Safety of Zoledronic Acid for the Treatment of Osteoporotic Children Treated With Glucocorticoids. | Baseline 1 (Visit 1 of the Core Study) through Month 24 (Visit 15/Final Extension Visit) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit) | 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. |
| Mean Change From Baseline 1 (Visit 1 of the Core Study) in Total Body BMC at Month 18 and 24 by Core Treatment Group. | Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit) | 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. |
| Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum P1NP at Month 18 and 24 by Core Treatment Group. | Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit) | 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. |
| Mean Change From Baseline 1 (Visit 1 of the Core Study) in BSAP at Month 18 and 24 by Core Treatment Group. | Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit) | 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. |
| Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum NTX at Month 18 and 24 by Core Treatment Group. | Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit) | 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. |
| 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. | Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit) | 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. |
| Number of Participants With New Vertebral Fractures During the 12 Month Extension Period by Core Treatment Group. | Month 24 (Visit 15/Final Extension Visit) | 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. |
| Number of Participants With New Morphometric Vertebral Fractures During the 12 Month Extension Period by Core Treatment Group. | Month 24 (Visit 15/Final Extension Visit) | 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). |
| 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. | Month 15, Month 18, Month 21, Month 24 | 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'. |
| Mean Change From Baseline (Core and Extension) in 2nd Metacarpal Cortical Width at Month 24 by Core Treatment Group. | 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) | 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. |
| Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum TRAP-5b at Month 18 and 24 by Core Treatment Group. | Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit) | 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. |
Countries
Australia, Canada, Hungary, Russia, South Africa, United Kingdom
Participant flow
Recruitment details
This study was conducted in 10 centers in 6 countries: Australia (1), Canada (4), Hungary (1), United Kingdom (1), Russian Federation (2), and South Africa (1).
Pre-assignment details
This was an open label extension to the Core study CZOL446H2337 (NCT00799266), where all patients received zoledronic acid. However, the study groups from the Core study were used to compare the patient populations within this extension phase, who received the same treatment under each particular group.
Participants by arm
| Arm | Count |
|---|---|
| Core Treatment Zoledronic Acid Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid | 10 |
| Core Treatment: Placebo Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid | 15 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Core Treatment Zoledronic Acid | Core Treatment: Placebo |
|---|---|---|---|
| Age, Continuous | 14.0 Years STANDARD_DEVIATION 3.21 | 15.3 Years STANDARD_DEVIATION 2.58 | 13.2 Years STANDARD_DEVIATION 3.38 |
| Bone specific alkaline phosphatase (BSAP) | 40.179 nanogram per milliliter (ng/mL) STANDARD_DEVIATION 31.7718 | 25.841 nanogram per milliliter (ng/mL) STANDARD_DEVIATION 14.8595 | 49.737 nanogram per milliliter (ng/mL) STANDARD_DEVIATION 36.658 |
| Lumbar Spine Bone Mineral Content (BMC) | 32.376 gram (g) STANDARD_DEVIATION 13.7584 | 42.106 gram (g) STANDARD_DEVIATION 15.6967 | 25.890 gram (g) STANDARD_DEVIATION 7.3089 |
| Lumbar Spine Bone Mineral Density (BMD) Z-score | -2.002 Z-score STANDARD_DEVIATION 1.0909 | -1.568 Z-score STANDARD_DEVIATION 1.0196 | -2.291 Z-score STANDARD_DEVIATION 1.0712 |
| Race/Ethnicity, Customized Black | 3 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 21 Participants | 8 Participants | 13 Participants |
| Race/Ethnicity, Customized Native American | 1 Participants | 0 Participants | 1 Participants |
| Second metacarpal cortical width | 0.41 millimeter (mm) STANDARD_DEVIATION 0.179 | 0.45 millimeter (mm) STANDARD_DEVIATION 0.207 | 0.38 millimeter (mm) STANDARD_DEVIATION 0.163 |
| Serum Cross linked N-telopeptide (NTX) | 35.967 nmol BCE/L STANDARD_DEVIATION 24.3991 | 19.092 nmol BCE/L STANDARD_DEVIATION 8.376 | 42.217 nmol BCE/L STANDARD_DEVIATION 25.2275 |
| Serum Procollagen type 1 amino-terminal propeptide (P1NP) | 370.880 nanogram per milliliter (ng/mL) STANDARD_DEVIATION 415.1329 | 141.300 nanogram per milliliter (ng/mL) STANDARD_DEVIATION 100.8111 | 523.933 nanogram per milliliter (ng/mL) STANDARD_DEVIATION 475.5547 |
| Serum Tartrate-resistant acid phosphatase isoform 5b (TRAP-5b) | 7.316 U/L STANDARD_DEVIATION 4.6283 | 5.338 U/L STANDARD_DEVIATION 2.5097 | 8.636 U/L STANDARD_DEVIATION 5.2925 |
| Sex: Female, Male Female | 8 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 17 Participants | 7 Participants | 10 Participants |
| Total body Bone Mineral Content (BMC) | 1485.011 gram (g) STANDARD_DEVIATION 605.2026 | 1976.698 gram (g) STANDARD_DEVIATION 636.2144 | 1144.613 gram (g) STANDARD_DEVIATION 253.5405 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 15 |
| other Total, other adverse events | 7 / 10 | 12 / 15 |
| serious Total, serious adverse events | 3 / 10 | 0 / 15 |
Outcome results
Primary
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.
Time frame: Baseline 1 (Visit 1 of the Core Study) through Month 24 (Visit 15/Final Extension Visit)
Population: The Safety population, which consisted of all patients who had been exposed to at least one infusion of study drug, was considered.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Core Treatment Zoledronic Acid | Long-term Safety of Zoledronic Acid for the Treatment of Osteoporotic Children Treated With Glucocorticoids. | On-treatment Adverse Events (AEs) | 7 Participants |
| Core Treatment Zoledronic Acid | Long-term Safety of Zoledronic Acid for the Treatment of Osteoporotic Children Treated With Glucocorticoids. | On-treatment Serious Adverse Events (SAEs) | 3 Participants |
| Core Treatment Zoledronic Acid | Long-term Safety of Zoledronic Acid for the Treatment of Osteoporotic Children Treated With Glucocorticoids. | On-treatment Deaths | 0 Participants |
| Core Treatment: Placebo | Long-term Safety of Zoledronic Acid for the Treatment of Osteoporotic Children Treated With Glucocorticoids. | On-treatment Adverse Events (AEs) | 12 Participants |
| Core Treatment: Placebo | Long-term Safety of Zoledronic Acid for the Treatment of Osteoporotic Children Treated With Glucocorticoids. | On-treatment Serious Adverse Events (SAEs) | 0 Participants |
| Core Treatment: Placebo | Long-term Safety of Zoledronic Acid for the Treatment of Osteoporotic Children Treated With Glucocorticoids. | On-treatment Deaths | 0 Participants |
Secondary
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.
Time frame: Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit)
Population: The Full Analysis population, which consisted of all randomized patients who had both Core Baseline and at least one post-baseline lumbar spine BMD Z-score in the Extension study, was considered.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Core Treatment Zoledronic Acid | Mean Change From Baseline 1 (Visit 1 of the Core Study) in BSAP at Month 18 and 24 by Core Treatment Group. | BSAP Change at Month 18 | -13.716 nanogram per milliliter (ng/mL) | Standard Error 8.5909 |
| Core Treatment Zoledronic Acid | Mean Change From Baseline 1 (Visit 1 of the Core Study) in BSAP at Month 18 and 24 by Core Treatment Group. | BSAP Change at Month 24 | -9.675 nanogram per milliliter (ng/mL) | Standard Error 6.4159 |
| Core Treatment: Placebo | Mean Change From Baseline 1 (Visit 1 of the Core Study) in BSAP at Month 18 and 24 by Core Treatment Group. | BSAP Change at Month 18 | 3.975 nanogram per milliliter (ng/mL) | Standard Error 8.0523 |
| Core Treatment: Placebo | Mean Change From Baseline 1 (Visit 1 of the Core Study) in BSAP at Month 18 and 24 by Core Treatment Group. | BSAP Change at Month 24 | -6.013 nanogram per milliliter (ng/mL) | Standard Error 5.9316 |
Comparison: BSAP Change at Month 18p-value: 0.212395% CI: [-41.925, 6.543]ANCOVA
Comparison: BSAP Change at Month 24p-value: 0.485295% CI: [-21.479, 14.155]ANCOVA
Secondary
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.
Time frame: Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit)
Population: The Full Analysis population, which consisted of all randomized patients who had both Core Baseline and at least one post-baseline lumbar spine BMD Z-score in the Extension study, was considered.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Core Treatment Zoledronic Acid | 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 BMC Change at Month 18 | 12.293 gram | Standard Error 1.7749 |
| Core Treatment Zoledronic Acid | 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 BMC Change at Month 24 | 15.845 gram | Standard Error 2.2217 |
| Core Treatment: Placebo | 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 BMC Change at Month 18 | 9.933 gram | Standard Error 1.6717 |
| Core Treatment: Placebo | 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 BMC Change at Month 24 | 14.666 gram | Standard Error 2.05 |
Comparison: Lumbar Spine BMC Change at Month 18p-value: 0.354495% CI: [-2.886, 7.606]ANCOVA
Comparison: Lumbar Spine BMC Change at Month 24p-value: 0.70595% CI: [-5.281, 7.639]ANCOVA
Secondary
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.
Time frame: Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit)
Population: The Full Analysis population, which consisted of all randomized patients who had both Core Baseline and at least one post-baseline lumbar spine BMD Z-score in the Extension study, was considered.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Core Treatment Zoledronic Acid | 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 BMD Z-score Change at Month 24 | -46.161 Z-score | Standard Error 12.4486 |
| Core Treatment Zoledronic Acid | 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 BMD Z-score Change at Month 18 | -40.648 Z-score | Standard Error 14.1205 |
| Core Treatment: Placebo | 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 BMD Z-score Change at Month 24 | -67.913 Z-score | Standard Error 12.1722 |
| Core Treatment: Placebo | 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 BMD Z-score Change at Month 18 | -44.348 Z-score | Standard Error 14.0348 |
Comparison: Lumbar Spine BMD Z-score Change at Month 18p-value: 0.850595% CI: [-37.242, 44.642]ANCOVA
Comparison: Lumbar Spine BMD Z-score Change at Month 24p-value: 0.21895% CI: [-14.126, 57.63]ANCOVA
Secondary
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.
Time frame: Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit)
Population: The Full Analysis population, which consisted of all randomized patients who had both Core Baseline and at least one post-baseline lumbar spine BMD Z-score in the Extension study, was considered.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Core Treatment Zoledronic Acid | Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum NTX at Month 18 and 24 by Core Treatment Group. | Serum NTX Change at Month 18 | -17.577 nmol BCE/L | Standard Error 168.8975 |
| Core Treatment Zoledronic Acid | Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum NTX at Month 18 and 24 by Core Treatment Group. | Serum NTX Change at Month 24 | -17.450 nmol BCE/L | Standard Error 2.3585 |
| Core Treatment: Placebo | Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum NTX at Month 18 and 24 by Core Treatment Group. | Serum NTX Change at Month 18 | -12.916 nmol BCE/L | Standard Error 168.8965 |
| Core Treatment: Placebo | Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum NTX at Month 18 and 24 by Core Treatment Group. | Serum NTX Change at Month 24 | -14.891 nmol BCE/L | Standard Error 2.059 |
Comparison: Serum NTX Change at Month 18p-value: 0.900995% CI: [-16.647, 7.325]ANCOVA
Comparison: Serum NTX Change at Month 24p-value: 0.947295% CI: [-8.864, 3.747]ANCOVA
Secondary
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.
Time frame: Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit)
Population: The Full Analysis population, which consisted of all randomized patients who had both Core Baseline and at least one post-baseline lumbar spine BMD Z-score in the Extension study, was considered.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Core Treatment Zoledronic Acid | Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum P1NP at Month 18 and 24 by Core Treatment Group. | Serum P1NP Change at Month 18 | -169.837 nanogram per milliliter (ng/mL) | Standard Error 86.864 |
| Core Treatment Zoledronic Acid | Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum P1NP at Month 18 and 24 by Core Treatment Group. | Serum P1NP Change at Month 24 | -228.068 nanogram per milliliter (ng/mL) | Standard Error 54.1402 |
| Core Treatment: Placebo | Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum P1NP at Month 18 and 24 by Core Treatment Group. | Serum P1NP Change at Month 18 | -22.157 nanogram per milliliter (ng/mL) | Standard Error 82.6761 |
| Core Treatment: Placebo | Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum P1NP at Month 18 and 24 by Core Treatment Group. | Serum P1NP Change at Month 24 | -95.631 nanogram per milliliter (ng/mL) | Standard Error 53.0765 |
Comparison: Serum P1NP Change at Month 18p-value: 0.414395% CI: [-394.41, 99.049]ANCOVA
Comparison: Serum P1NP Change at Month 24p-value: 0.126695% CI: [-286.452, 21.579]ANCOVA
Secondary
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.
Time frame: Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit)
Population: The Full Analysis population, which consisted of all randomized patients who had both Core Baseline and at least one post-baseline lumbar spine BMD Z-score in the Extension study, was considered.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Core Treatment Zoledronic Acid | 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 TRAP-5b Change at Month 24 | -2.670 U/L | Standard Error 0.7158 |
| Core Treatment Zoledronic Acid | 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 TRAP-5b Change at Month 18 | -2.661 U/L | Standard Error 0.8126 |
| Core Treatment: Placebo | 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 TRAP-5b Change at Month 24 | -2.260 U/L | Standard Error 0.6701 |
| Core Treatment: Placebo | 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 TRAP-5b Change at Month 18 | -1.179 U/L | Standard Error 0.7725 |
Comparison: Serum TRAP-5b Change at Month 18p-value: 0.4695% CI: [-3.805, 0.841]ANCOVA
Comparison: Serum TRAP-5b Change at Month 24p-value: 0.923695% CI: [-2.423, 1.603]ANCOVA
Secondary
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.
Time frame: Month 18 (Visit 12 of the Extension Study), Month 24 (Visit 15/Final Extension Visit)
Population: The Full Analysis population, which consisted of all randomized patients who had both Core Baseline and at least one post-baseline lumbar spine BMD Z-score in the Extension study, was considered.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Core Treatment Zoledronic Acid | 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 Change at Month 18 | 387.721 gram | Standard Error 87396.2756 |
| Core Treatment Zoledronic Acid | 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 Change at Month 24 | 496.997 gram | Standard Error 120.9281 |
| Core Treatment: Placebo | 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 Change at Month 24 | 431.323 gram | Standard Error 123.5462 |
| Core Treatment: Placebo | 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 Change at Month 18 | 266.592 gram | Standard Error 87396.2698 |
Comparison: Total body BMC Change at Month 18p-value: 0.53195% CI: [-291, 533.258]ANCOVA
Comparison: Total body BMC Change at Month 24p-value: 0.734795% CI: [-344.067, 475.415]ANCOVA
Secondary
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.
Time frame: 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)
Population: The Full Analysis population, which consisted of all randomized patients who had both Core Baseline and at least one post-baseline lumbar spine BMD Z-score in the Extension study, was considered.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Core Treatment Zoledronic Acid | Mean Change From Baseline (Core and Extension) in 2nd Metacarpal Cortical Width at Month 24 by Core Treatment Group. | 2nd metacarpal cortical width change from BL1 | -0.04 millimeter (mm) | Standard Error 0.068 |
| Core Treatment Zoledronic Acid | Mean Change From Baseline (Core and Extension) in 2nd Metacarpal Cortical Width at Month 24 by Core Treatment Group. | 2nd metacarpal cortical width change from BL2 | -0.09 millimeter (mm) | Standard Error 0.089 |
| Core Treatment: Placebo | Mean Change From Baseline (Core and Extension) in 2nd Metacarpal Cortical Width at Month 24 by Core Treatment Group. | 2nd metacarpal cortical width change from BL1 | -0.03 millimeter (mm) | Standard Error 0.054 |
| Core Treatment: Placebo | Mean Change From Baseline (Core and Extension) in 2nd Metacarpal Cortical Width at Month 24 by Core Treatment Group. | 2nd metacarpal cortical width change from BL2 | 0.02 millimeter (mm) | Standard Error 0.063 |
Comparison: 2nd metacarpal cortical width chge from BL1 at Month 24p-value: 0.923195% CI: [-0.18, 0.17]ANCOVA
Comparison: 2nd metacarpal cortical width chge from BL2 at Month 24p-value: 0.269495% CI: [-0.32, 0.1]ANCOVA
Secondary
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).
Time frame: Month 24 (Visit 15/Final Extension Visit)
Population: The Full Analysis population, which consisted of all randomized patients who had both Core Baseline and at least one post-baseline lumbar spine BMD Z-score in the Extension study, was considered.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Core Treatment Zoledronic Acid | Number of Participants With New Morphometric Vertebral Fractures During the 12 Month Extension Period by Core Treatment Group. | 1 Participants |
| Core Treatment: Placebo | Number of Participants With New Morphometric Vertebral Fractures During the 12 Month Extension Period by Core Treatment Group. | 1 Participants |
Comparison: New morphometric vertebral fractures at Month 12 Extensionp-value: 1Fisher Exact
Secondary
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.
Time frame: Month 24 (Visit 15/Final Extension Visit)
Population: The Full Analysis population, which consisted of all randomized patients who had both Core Baseline and at least one post-baseline lumbar spine BMD Z-score in the Extension study, was considered.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Core Treatment Zoledronic Acid | Number of Participants With New Vertebral Fractures During the 12 Month Extension Period by Core Treatment Group. | 1 Participants |
| Core Treatment: Placebo | Number of Participants With New Vertebral Fractures During the 12 Month Extension Period by Core Treatment Group. | 1 Participants |
Comparison: New vertebral fractures at Month 12 Extensionp-value: 1Fisher Exact
Secondary
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'.
Time frame: Month 15, Month 18, Month 21, Month 24
Population: The Full Analysis population, which consisted of all randomized patients who had both Core Baseline and at least one post-baseline lumbar spine BMD Z-score in the Extension study, was considered.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Core Treatment Zoledronic Acid | 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. | Reduction in Pain at Month 24 | 30.0 Percentage of Patients |
| Core Treatment Zoledronic Acid | 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. | Reduction in Pain at Month 15 | 55.6 Percentage of Patients |
| Core Treatment Zoledronic Acid | 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. | Reduction in Pain at Month 18 | 30.0 Percentage of Patients |
| Core Treatment Zoledronic Acid | 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. | Reduction in Pain at Month 21 | 30.0 Percentage of Patients |
| Core Treatment: Placebo | 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. | Reduction in Pain at Month 21 | 50.0 Percentage of Patients |
| Core Treatment: Placebo | 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. | Reduction in Pain at Month 24 | 38.5 Percentage of Patients |
| Core Treatment: Placebo | 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. | Reduction in Pain at Month 18 | 50.0 Percentage of Patients |
| Core Treatment: Placebo | 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. | Reduction in Pain at Month 15 | 46.2 Percentage of Patients |
Comparison: Reduction in Pain at Month 15p-value: 0.397195% CI: [0.13, 173.07]Regression, Logistic
Comparison: Reduction in Pain at Month 18p-value: 0.604695% CI: [0.01, 999.99]Regression, Logistic
Comparison: Reduction in Pain at Month 21p-value: 0.604695% CI: [0.01, 999.99]Regression, Logistic
Comparison: Reduction in Pain at Month 24p-value: 0.87595% CI: [0.05, 38.04]Regression, Logistic