E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of osteoporosis in a paediatric population (aged 5 to 19 years old) treated with systemic glucocorticoids (i.v. or oral) |
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E.1.1.1 | Medical condition in easily understood language |
Disease of bones that leads to an increase risk of fracture |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10031282 |
E.1.2 | Term | Osteoporosis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
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E.2.2 | Secondary objectives of the trial |
To evaluate
Group 1
•change from baseline1(Core study) in LS areal BMD Z-score, LS and total body BMC at Month 18 & 24
• the change from baseline1 in serum P1NP, NTX, BSAP and TRAP-5b at Month 18 & 24
•change from baseline1 in pain using FPS-R at Month 15, 18, 21 & 24
•change from baseline1 in bone age & 2nd metacarpal cortical width at month 24
Group 2:
•change from baseline2 (Extension study) in LS areal BMD Z-score, LS and total body BMC at Month 6 & 12
•change from baseline2 in serum P1NP, NTX, BSAP and TRAP-5b) at Month 6 & 12
•change from baseline2 in pain using FPS-R at Month 3, 6, 9 & 12
•change from baseline2 in bone age and 2nd metacarpal cortical width at month 12
Both groups:
•proportion of patients with new clinical vertebral fractures and new morphometric vertebral fracture during 12 month period.
To demonstrate zoledronic acid is safe for treatment of osteoporotic children treated with glucocorticoids |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Signed consent/assent to study participation.
Group 1:
•Children and adolescents, male or female, between 6 to 19 years of age who met the inclusion criteria for entry into the Core study and who took at least one dose of study drug in 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 at Visit 5 of the Core study.
• Patients who followed the regimen of calcium and vitamin D intake as required in the Core study
Group 2 :
• Children and adolescents, male or female, between 5 to 17 years of age 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 Investigator’s 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)
• Lumbar Spine-BMD Z-score of - 0.5 or worse confirmed by the central imaging
• Evidence of at least 1 vertebral compression fracture (at least Genant Grade 1 vertebral compression or radiographic signs of vertebral compression*) seen on X-ray within 1 month of or at screening visit confirmed by central reading.
*Radiographic signs of vertebral compression fracture include loss of endplate parallelism, vertebral buckling and endplate interruption. |
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E.4 | Principal exclusion criteria |
• Patients who demonstrated a 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)
• Vitamin D deficiency (serum 25-hydroxy vitamin D concentration of <20 ng/ml or <50 nmol/L) at Visit 8 (Group 1) or Visit 8A (Group 2)
• Hypocalcaemia and hypophosphatemia: any value (age-matched) below the normal range 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 based on the Schwartz formula at Visit 8 (Group 1) or Visit 8A (Group 2). 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety assessments will consist of:
• monitoring and recording of all adverse events and serious adverse events,
• the performance of physical examinations including oral examinations for exposed bone.
• the regular laboratory monitoring of hematology, blood chemistry and urinalysis, regular measurement of vital signs, and
• renal function (serum creatinine & GFR).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Monitoring and recording of all adverse events and serious adverse events:
At each visit during the study
• Physical examination including oral examination:
At visits 9, 12 and Visit 15
• Vital signs:
Blood pressure and pulse rate: Visits 8 (Group 1 only), 8A (Group 2 only), Visits 9, 12 and 15
• Sitting and standing height and weight measurements: Visits 8 (Group 1 only), 8A (Group 2 only), Visits 9, 12 and 15
• Laboratory evaluations:
Central laboratory test (hematology, biochemistry and urinalysis): Visits 8A (Group 2 only), Visits 9, 12 and 15.
Additional lab test for renal monitoring: Visits 9, 10, 12, 13 and 15. |
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E.5.2 | Secondary end point(s) |
The efficacy variables will be measured using the following techniques:
• vertebral morphometric fractures
• clinical fractures
• DXA measurements
• bone marker analysis
• height measurements
• bone age and metacarpal cortical width assessment
• pain assessment
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Vertebral morphometric fractures:
At final visit of Core study (Group1) or Visit 8A (Group2) and Visit 15
•Clinical fractures:
At final visit of the Core study (Group 1) or Visit 8A (Group2) and at each Visits
•DXA measurements:
At final visit of Core study (Group 1) or Visit 8A (for Group 2), Visit 9 and 15.
•Bone marker Analysis:
At final visit of Core study (Group 1) or Visit 9 (Group 2), Visit 12 and 15
•Height measurements:
At final visit of Core study (Group 1) or Visit 8A/or 9 (Group 2), Visit 12 and 15
•Bone age and metacarpal carpal cortical width assessment:
At final visit of Core study (Group 1) or Visit 8A (Group 2) and Visit 15.
•Pain Assessment:
At final visit of Core study (Group 1) and Visit 9, 11, 12, 14 and 15. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Germany |
Hungary |
Italy |
Poland |
Russian Federation |
South Africa |
Turkey |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last Visit of the Last Subject |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 12 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 12 |