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CompletedNCT01197300Updated Sep 20, 2019Results posted

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

A Phase 3 interventional study of Zoledronic acid in Osteoporosis, sponsored by Novartis Pharmaceuticals. Completed at 10 sites in 6 countries. Open to participants aged 5 Years to 19 Years. Per ClinicalTrials.gov, last updated 2019-09-20.

Sponsored by Novartis Pharmaceuticals · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
25
Allocation
Not applicable
Ages
5 Years to 19 Years
Sex
All
01

Study 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.

02

Conditions studied

  • Osteoporosis

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Keywords

  • Osteoporosis, children and adolescents, zoledronic acid, chronic inflammation, Duchenne muscular dystrophy, glucocorticoids, chronic inflammatory conditions
03

In context

Osteoporosis

1,640 studies on the registry are indexed under Osteoporosis; 212 are open to participants now.

This study's enrollment of 25 is below the median of 95 across 1,133 interventional studies indexed under Osteoporosis.

Browse Osteoporosis studies →

Lead sponsor

Novartis Pharmaceuticals is the lead sponsor of 2,673 studies on the registry; 228 are open to participants now.

Of its 576 completed or terminated interventional studies of FDA-regulated products, 431 (75%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
5 Years to 19 Years
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility 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.
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
25 participants (actual)

Study arms

  • 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

Interventions

  • DrugZoledronic acid

    intravenous infusion

06

What researchers measure

Primary outcomes

  1. 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)

Secondary outcomes

  1. 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)

  2. 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)

  3. 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)

  4. 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)

  5. 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)

  6. 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)

  7. 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)

  8. 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)

  9. 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)

  10. 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

  11. 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)

07

Results

Posted Sep 20, 2019

Participant flow

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).

Participant flow — Overall Study
MilestoneCore Treatment Zoledronic AcidCore Treatment: Placebo
Started1015
Completed1013
Not completed02
Withdrew: Lost to follow-up01
Withdrew: Protocol violation01

Outcome measures

PrimaryLong-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)
Reported as:
Count of participants · Participants
Long-term Safety of Zoledronic Acid for the Treatment of Osteoporotic Children Treated With Glucocorticoids.
ParticipantsCore Treatment Zoledronic AcidCore Treatment: Placebo
On-treatment Adverse Events (AEs)712
On-treatment Serious Adverse Events (SAEs)30
On-treatment Deaths00
SecondaryMean 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)
Reported as:
Least squares mean · Z-score
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.
Z-scoreCore Treatment Zoledronic AcidCore Treatment: Placebo
Lumbar Spine BMD Z-score Change at Month 18-40.648 ± 14.1205-44.348 ± 14.0348
Lumbar Spine BMD Z-score Change at Month 24-46.161 ± 12.4486-67.913 ± 12.1722
Statistical analysis
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.8505 (An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Core baseline lumbar spine BMD Z-score as explanatory variables and pooled centers as random effect.) · Difference in ls mean: 3.700 · 95% CI -37.242 to 44.642
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.2180 (An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Core baseline lumbar spine BMD Z-score as explanatory variables and pooled centers as random effect.) · Difference in ls mean: 21.752 · 95% CI -14.126 to 57.630
SecondaryMean 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)
Reported as:
Least squares mean · gram
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.
gramCore Treatment Zoledronic AcidCore Treatment: Placebo
Lumbar Spine BMC Change at Month 1812.293 ± 1.77499.933 ± 1.6717
Lumbar Spine BMC Change at Month 2415.845 ± 2.221714.666 ± 2.0500
Statistical analysis
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.3544 (An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Core baseline lumbar spine BMD Z-score as explanatory variables and pooled centers as random effect.) · Difference in ls mean: 2.360 · 95% CI -2.886 to 7.606
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.7050 (An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Core baseline lumbar spine BMD Z-score as explanatory variables and pooled centers as random effect.) · Difference in ls mean: 1.179 · 95% CI -5.281 to 7.639
SecondaryMean 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)
Reported as:
Least squares mean · gram
Mean Change From Baseline 1 (Visit 1 of the Core Study) in Total Body BMC at Month 18 and 24 by Core Treatment Group.
gramCore Treatment Zoledronic AcidCore Treatment: Placebo
Total body BMC Change at Month 18387.721 ± 87396.2756266.592 ± 87396.2698
Total body BMC Change at Month 24496.997 ± 120.9281431.323 ± 123.5462
Statistical analysis
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.5310 (An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Core baseline lumbar spine BMD Z-score as explanatory variables and pooled centers as random effect.) · Difference in ls mean: 121.129 · 95% CI -291.000 to 533.258
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.7347 (An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Core baseline lumbar spine BMD Z-score as explanatory variables and pooled centers as random effect.) · Difference in ls mean: 65.674 · 95% CI -344.067 to 475.415
SecondaryMean 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)
Reported as:
Least squares mean · nanogram per milliliter (ng/mL)
Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum P1NP at Month 18 and 24 by Core Treatment Group.
nanogram per milliliter (ng/mL)Core Treatment Zoledronic AcidCore Treatment: Placebo
Serum P1NP Change at Month 18-169.837 ± 86.8640-22.157 ± 82.6761
Serum P1NP Change at Month 24-228.068 ± 54.1402-95.631 ± 53.0765
Statistical analysis
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.4143 (An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.) · Difference in ls mean: -147.680 · 95% CI -394.410 to 99.049The transformed data was calculated by dividing the post-baseline value by the baseline value and then applying the loge transformation
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.1266 (An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.) · Difference in ls mean: -132.437 · 95% CI -286.452 to 21.579The transformed data was calculated by dividing the post-baseline value by the baseline value and then applying the loge transformation
SecondaryMean 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)
Reported as:
Least squares mean · nanogram per milliliter (ng/mL)
Mean Change From Baseline 1 (Visit 1 of the Core Study) in BSAP at Month 18 and 24 by Core Treatment Group.
nanogram per milliliter (ng/mL)Core Treatment Zoledronic AcidCore Treatment: Placebo
BSAP Change at Month 18-13.716 ± 8.59093.975 ± 8.0523
BSAP Change at Month 24-9.675 ± 6.4159-6.013 ± 5.9316
Statistical analysis
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.2123 (An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.) · Difference in ls mean: -17.691 · 95% CI -41.925 to 6.543The transformed data was calculated by dividing the post-baseline value by the baseline value and then applying the loge transformation
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.4852 (An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.) · Difference in ls mean: -3.662 · 95% CI -21.479 to 14.155The transformed data was calculated by dividing the post-baseline value by the baseline value and then applying the loge transformation
SecondaryMean 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)
Reported as:
Least squares mean · nmol BCE/L
Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum NTX at Month 18 and 24 by Core Treatment Group.
nmol BCE/LCore Treatment Zoledronic AcidCore Treatment: Placebo
Serum NTX Change at Month 18-17.577 ± 168.8975-12.916 ± 168.8965
Serum NTX Change at Month 24-17.450 ± 2.3585-14.891 ± 2.0590
Statistical analysis
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.9009 (An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.) · Difference in ls mean: -4.661 · 95% CI -16.647 to 7.325The transformed data was calculated by dividing the post-baseline value by the baseline value and then applying the loge transformation
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.9472 (An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.) · Difference in ls mean: -2.558 · 95% CI -8.864 to 3.747The transformed data was calculated by dividing the post-baseline value by the baseline value and then applying the loge transformation
SecondaryMean 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)
Reported as:
Least squares mean · U/L
Mean Change From Baseline 1 (Visit 1 of the Core Study) in Serum TRAP-5b at Month 18 and 24 by Core Treatment Group.
U/LCore Treatment Zoledronic AcidCore Treatment: Placebo
Serum TRAP-5b Change at Month 18-2.661 ± 0.8126-1.179 ± 0.7725
Serum TRAP-5b Change at Month 24-2.670 ± 0.7158-2.260 ± 0.6701
Statistical analysis
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.4600 (An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.) · Difference in ls mean: -1.482 · 95% CI -3.805 to 0.841The transformed data was calculated by dividing the post-baseline value by the baseline value and then applying the loge transformation
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.9236 (An analysis of covariance (ANCOVA) model was performed on the transformed data with Core treatment, pooled centers, underlying condition treated with glucocorticoids and loge as explanatory variables and pooled centers as random effect.) · Difference in ls mean: -0.410 · 95% CI -2.423 to 1.603The transformed data was calculated by dividing the post-baseline value by the baseline value and then applying the loge transformation
SecondaryNumber 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)
Reported as:
Count of participants · Participants
Number of Participants With New Vertebral Fractures During the 12 Month Extension Period by Core Treatment Group.
ParticipantsCore Treatment Zoledronic AcidCore Treatment: Placebo
Number of Participants With New Vertebral Fractures During the 12 Month Extension Period by Core Treatment Group.11
Statistical analysis
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · Fisher Exact · p = 1.0000
SecondaryNumber 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)
Reported as:
Count of participants · Participants
Number of Participants With New Morphometric Vertebral Fractures During the 12 Month Extension Period by Core Treatment Group.
ParticipantsCore Treatment Zoledronic AcidCore Treatment: Placebo
Number of Participants With New Morphometric Vertebral Fractures During the 12 Month Extension Period by Core Treatment Group.11
Statistical analysis
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · Fisher Exact · p = 1.0000
SecondaryPercentage 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
Reported as:
Number · Percentage of Patients
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.
Percentage of PatientsCore Treatment Zoledronic AcidCore Treatment: Placebo
Reduction in Pain at Month 1555.646.2
Reduction in Pain at Month 1830.050.0
Reduction in Pain at Month 2130.050.0
Reduction in Pain at Month 2430.038.5
Statistical analysis
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · Regression, Logistic · p = 0.3971 (Presented by treatment group and evaluated using a logistic regression model with Core treatment, pooled centers, underlying condition treated with glucocorticoids and Core baseline pain score as explanatory variables.) · Odds ratio (or): 4.73 · 95% CI 0.13 to 173.07
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · Regression, Logistic · p = 0.6046 (Presented by treatment group and evaluated using a logistic regression model with Core treatment, pooled centers, underlying condition treated with glucocorticoids and Core baseline pain score as explanatory variables.) · Odds ratio (or): 0.01 · 95% CI 0.01 to 999.99
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · Regression, Logistic · p = 0.6046 (Presented by treatment group and evaluated using a logistic regression model with Core treatment, pooled centers, underlying condition treated with glucocorticoids and Core baseline pain score as explanatory variables.) · Odds ratio (or): 0.01 · 95% CI 0.01 to 999.99
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · Regression, Logistic · p = 0.8750 (Presented by treatment group and evaluated using a logistic regression model with Core treatment, pooled centers, underlying condition treated with glucocorticoids and Core baseline pain score as explanatory variables.) · Odds ratio (or): 1.31 · 95% CI 0.05 to 38.04
SecondaryMean 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)
Reported as:
Least squares mean · millimeter (mm)
Mean Change From Baseline (Core and Extension) in 2nd Metacarpal Cortical Width at Month 24 by Core Treatment Group.
millimeter (mm)Core Treatment Zoledronic AcidCore Treatment: Placebo
2nd metacarpal cortical width change from BL1-0.04 ± 0.068-0.03 ± 0.054
2nd metacarpal cortical width change from BL2-0.09 ± 0.0890.02 ± 0.063
Statistical analysis
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.9231 (An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Core baseline bone age as explanatory variables and pooled centers as random effect.) · Difference in ls mean: -0.01 · 95% CI -0.18 to 0.17
  • Core Treatment Zoledronic Acid vs Core Treatment: Placebo · ANCOVA · p = 0.2694 (An analysis of covariance (ANCOVA) model was performed with Core treatment, pooled centers, underlying condition treated with GCs and Extension baseline bone age as explanatory variables and pooled centers as random effect.) · Difference in ls mean: -0.11 · 95% CI -0.32 to 0.10

Adverse events

Collected over Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 13 months.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Core Treatment Zoledronic Acid0/10 (0%)3/10 (30%)7/10 (70%)
Core Treatment Placebo0/15 (0%)0/15 (0%)12/15 (80%)
Most frequent serious events
Most frequent serious events
EventCore Treatment Zoledronic AcidCore Treatment Placebo
DiarrhoeaGastrointestinal disorders1/100/15
NauseaGastrointestinal disorders1/100/15
VomitingGastrointestinal disorders1/100/15
Postictal stateNervous system disorders1/100/15
Status epilepticusNervous system disorders1/100/15
DepressionPsychiatric disorders1/100/15
Suicide attemptPsychiatric disorders1/100/15
Most frequent other events
Showing 10 of 66
Most frequent other events
EventCore Treatment Zoledronic AcidCore Treatment Placebo
ArthralgiaMusculoskeletal and connective tissue disorders0/105/15
HeadacheNervous system disorders3/102/15
Abdominal painGastrointestinal disorders2/102/15
NauseaGastrointestinal disorders1/103/15
VomitingGastrointestinal disorders2/101/15
Chest painGeneral disorders2/100/15
FatigueGeneral disorders0/103/15
PyrexiaGeneral disorders2/103/15
InfluenzaInfections and infestations1/103/15
Back painMusculoskeletal and connective tissue disorders1/103/15

Baseline characteristics

Age, Continuous
Age, Continuous(Years)Core Treatment Zoledronic AcidCore Treatment: PlaceboTotal
Mean15.3 ± 2.5813.2 ± 3.3814.0 ± 3.21
Sex: Female, Male
Sex: Female, Male(Participants)Core Treatment Zoledronic AcidCore Treatment: PlaceboTotal
Female358
Male71017
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Core Treatment Zoledronic AcidCore Treatment: PlaceboTotal
Caucasian81321
Black213
Native American011
Lumbar Spine Bone Mineral Density (BMD) Z-score
Lumbar Spine Bone Mineral Density (BMD) Z-score(Z-score)Core Treatment Zoledronic AcidCore Treatment: PlaceboTotal
Mean-1.568 ± 1.0196-2.291 ± 1.0712-2.002 ± 1.0909
Lumbar Spine Bone Mineral Content (BMC)
Lumbar Spine Bone Mineral Content (BMC)(gram (g))Core Treatment Zoledronic AcidCore Treatment: PlaceboTotal
Mean42.106 ± 15.696725.890 ± 7.308932.376 ± 13.7584
Total body Bone Mineral Content (BMC)
Total body Bone Mineral Content (BMC)(gram (g))Core Treatment Zoledronic AcidCore Treatment: PlaceboTotal
Mean1976.698 ± 636.21441144.613 ± 253.54051485.011 ± 605.2026
Serum Procollagen type 1 amino-terminal propeptide (P1NP)
Serum Procollagen type 1 amino-terminal propeptide (P1NP)(nanogram per milliliter (ng/mL))Core Treatment Zoledronic AcidCore Treatment: PlaceboTotal
Mean141.300 ± 100.8111523.933 ± 475.5547370.880 ± 415.1329
Bone specific alkaline phosphatase (BSAP)
Bone specific alkaline phosphatase (BSAP)(nanogram per milliliter (ng/mL))Core Treatment Zoledronic AcidCore Treatment: PlaceboTotal
Mean25.841 ± 14.859549.737 ± 36.658040.179 ± 31.7718

3 further baseline measures are reported on the registry.

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Study locations

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

Publications

  • Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR; HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007 May 3;356(18):1809-22. doi: 10.1056/NEJMoa067312. PubMed 17476007 ↗
  • Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med. 1998 Oct 1;339(14):947-52. doi: 10.1056/NEJM199810013391402. PubMed 9753709 ↗
  • Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest. 1999 Nov;104(10):1363-74. doi: 10.1172/JCI6800. PubMed 10562298 ↗
  • Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, Widmer A, Devogelaer JP, Kaufman JM, Jaeger P, Body JJ, Brandi ML, Broell J, Di Micco R, Genazzani AR, Felsenberg D, Happ J, Hooper MJ, Ittner J, Leb G, Mallmin H, Murray T, Ortolani S, Rubinacci A, Saaf M, Samsioe G, Verbruggen L, Meunier PJ. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med. 2002 Feb 28;346(9):653-61. doi: 10.1056/NEJMoa011807. PubMed 11870242 ↗
  • Ward L, Tricco AC, Phuong P, Cranney A, Barrowman N, Gaboury I, Rauch F, Tugwell P, Moher D. Bisphosphonate therapy for children and adolescents with secondary osteoporosis. Cochrane Database Syst Rev. 2007 Oct 17;2007(4):CD005324. doi: 10.1002/14651858.CD005324.pub2. PubMed 17943849 ↗

Study documents

  • Study protocol · May 18, 2016
  • Statistical analysis plan · Jun 4, 2018

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — 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

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Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Sep 20, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
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Registry details

Key details

Study ID
NCT01197300
Lead sponsor
Novartis Pharmaceuticals
Responsible party
Sponsor
First posted
Sep 9, 2010
Start date
Oct 25, 2010
Primary completion
Feb 27, 2019
Completion
Feb 27, 2019
Results posted
Sep 20, 2019
Last update
Sep 20, 2019

Study contacts

Novartis Pharmaceuticals
study director · Novartis Pharmaceuticals

Oversight

Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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