E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 10031243 |
E.1.2 | Term | Osteogenesis imperfecta |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of denosumab on lumbar spine bone mineral density (BMD) Z-score at 12 months, as assessed by dual-energy X-ray absorptiometry (DXA), in children 2 to 17 years of age (at the time of screening) on a 3-Month Dosing Regimen with osteogenesis imperfecta (OI). |
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E.2.2 | Secondary objectives of the trial |
To evaluate denosumab in children 2 to 17 years of age with OI on a 3-Month Dosing Regimen with respect to: - Change in lumbar spine BMD Z-score, at 6 months - Change in proximal femur BMD Z-score, at 6 and 12 months - Incidence of X-ray confirmed long bone and new and worsening vertebral fractures from pre to post-treatment at 12 months Incidence of improving vertebral fractures from pre to post-treatment at 12 months - Incidence of pretreatment compared with post-treatment vertebral and non-vertebral fractures at 12 months - Change in Child Health Questionnaire–Parent Form-50 Physical Summary score at 12 months - Change in CHQ-PF-50 Psychological Summary score at 12 months - Change in Childhood Health Assessment Questionnaire Disability Index score at 12 months - Change in Wong-Baker Faces Pain Rating Scale 12 months - Change in growth velocity at 12 months - Serum denosumab concentration and bone turnover markers after the first dose of 3-Month Dosing Regimen and every 3 months |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PK/bone turnover markers (BTM) substudy of approximately 50 subjects to - determine serum concentration of denosumab at 1 and 10 days and 6, 12, 18, 24, 30, and 36 months in all subjects - evaluate changes observed in bone turnover markers (bone-specific alkaline phosphatase [BSAP], serum type I collagen C-telopeptide [sCTX]) |
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E.3 | Principal inclusion criteria |
- Informed consent (to be provided by parent or legal guardian) and informed assent (to be provided by subjects when age-appropriate). - Children aged 2 to 17 years inclusive at screening - Clinical diagnosis of OI defined as a clinical history consistent with type I-IV OI as determined by presence of expected phenotype (examples include: facial shape, voice, blue sclera, dentinogenesis imperfecta, typical radiographic features, fracture pattern) and lack of additional features unrelated to type I-IV OI (eg, blindness, mental retardation, neuropathy, craniosynostosis; premature exfoliation of deciduous teeth) o* If familial, also must be autosomal dominant - Clinical severity of OI as defined by o 2 or more prevalent vertebral compression fractures; OR o 1 prevalent vertebral compression fracture and 1 or more nonvertebral fractures within the previous 2 years; OR o 3 or more fractures within the previous 2 years |
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E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria at screening are not eligible for enrollment: - Inability or unwillingness to comply with the requirements for frequent calcium and phosphorus monitoring for 14 days after the first dose of denosumab (only applies to the first 5 subjects age 11 to17 enrolled in the study and the first 5 subjects of any age meeting the criteria for increased bone turnover (see Section 2.3.2.1) - Currently unhealed fracture or osteotomy as defined by orthopedic opinion - Osteotomy within 5 months of screening - Evidence of untreated oral cavities or oral infections - Recent or planned invasive dental procedure - Surgical tooth extraction which has not healed by screening - History of an electrophoresis pattern inconsistent with type I to IV OI - History of known mutation in a gene other than COL1A1/COL1A2 causing OI or metabolic bone disease - Abnormalities of the following per central laboratory reference ranges at screening: o Serum albumin corrected calcium < lower limit of normal (LLN) o Serum vitamin D < 20 ng/mL; re-screening for Vitamin D level < 20 ng/mL will be allowed, after adequate supplementation o Aspartate aminotransferase (AST), alanine aminotransferase (ALT) > 1.5 x upper limit of normal (ULN) o Total bilirubin (TBL) > 1.5 x ULN (subjects with Gilbert syndrome are eligible) o Serum phosphorus < LLN o Serum alkaline phosphatase > 20% above the ULN or > 20% below the LLN - Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (calculated by the Schwartz equation at screening) - Evidence of any of the following: o Current hyperthyroidism (unless well-controlled on stable antithyroid therapy) o Current clinical hypothyroidism (unless well-controlled on stable thyroid replacement therapy) o History of hyperparathyroidism o Current hypoparathyroidism o Current, uncontrolled hypercalcemia (albumin-corrected serum Ca >10% ULN) o Current metaphyseal index Z-score > +1 o History of osteomalacia or rickets (chart review) o Other bone diseases that affect bone metabolism (eg, osteoporosis pseudoglioma syndrome, idiopathic juvenile osteoporosis, osteopetrosis, hypophosphatasia) o History of autoimmune disease o History of malabsorption (in children with serum albumin < LLN, malabsorption should be clinically ruled out by the PI to confirm eligibility) o History of rare hereditary problems of fructose intolerance o History of long QT syndrome o History of non-healing osteotomy o History of malignancy o History of alcohol or drug abuse o History of any solid organ or bone marrow transplant o Contraindicated or poorly tolerant of denosumab therapy - Positive blood screen for human immunodeficiency virus -1 or -2 antibody - Positive blood screen for hepatitis B surface antigen or hepatitis C antibody - Currently pregnant or planning a pregnancy during the study and for an additional 5 months after the last dose of denosumab - For sexually active girls: refusal to use highly effective methods of contraception and to continue this practice for 5 months after the last injection of denosumab |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in lumbar spine BMD Z-score, as assessed by DXA, at 12 months in subjects receiving the 3-Month Dosing Regimen. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Change from baseline in lumbar spine BMD Z-score, as assessed by DXA, at 6 months in subjects receiving the 3-Month Dosing Regimen - Change from baseline in proximal femur BMD Z-score, as assessed by DXA, at 6 and 12 months (in subjects 5 years of age and older) in subjects receiving the 3-Month Dosing Regimen - Incidence of X-ray confirmed long bone and new and worsening vertebral fractures from pretreatment (on 6-Month Dosing Regimen to post-treatment on 3-Month Dosing Regimen at 12 months) - Subject incidence of improving vertebral fractures from pretreatment on 6-Month Dosing Regimen to post-treatment on 3-Month Dosing Regimen at 12 months - Incidence of vertebral and nonvertebral fractures from pretreatment on 6-Month Dosing Regimen to post-treatment on 3-Month Dosing Regimen at 12 months - Change from baseline in CHQ-PF-50 Physical Summary score at 12 months in subjects receiving the 3-Month Dosing Regimen - Change from baseline in CHQ-PF-50 Psychological Summary score at 12 months in subjects receiving the 3-Month Dosing Regimen - Change from baseline in CHAQ Disability Index score at 12 months in subjects receiving the 3-Month Dosing Regimen Change from baseline in WBFPRS at 12 months in subjects receiving the 3-Month Dosing Regimen - Change from baseline in growth velocity (determined by calculating age-months in subjects receiving the 3-Month Dosing Regimen - Serum concentration of denosumab and serum bone turnover markers on days 1, 10, 30, 60, and every 3 months in subjects on 3-Month Dosing Regimen - Serum concentration of denosumab at 1, 10, and 30 days, and 3, 6, and 9 months (PK/BTM substudy; 6-Month Dosing Regimen) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | No |
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 |
Bulgaria |
Canada |
Czech Republic |
France |
Germany |
Hungary |
Poland |
Spain |
United Kingdom |
United States |
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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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the end of the trial is defined as the date when the last subject is last assessed for evaluation in the study, which corresponds to the month 36 visit. |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |