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 in 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 OI. |
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E.2.2 | Secondary objectives of the trial |
Change in lumbar spine BMD Z-score, 6M Change in proximal femur BMD Z-score 6, 12M Incidence of long bone, new and worsening vertebral fractures from 12M on 6-M Dosing Regimen to 12M on 3-M Dosing Regimen Incidence of new and worsening vertebral fractures from last 12M on 6-M Dosing Regimen to 12M on 3-M Dosing Regimen Incidence of X-ray confirmed new vertebral fractures from 12M on 6-M Dosing Regimen to 12M on 3-M Dosing Regimen Incidence of confirmed improving vertebral fractures from baseline of 3M Dosing Regimen to 12M on 3-M Dosing Regimen Incidence of vertebral and nonvertebral fractures from 12M on 6-M Dosing Regimen to 12M on 3-M Dosing Regimen Change in CHQ-PF-50 Physical Summary score 12 months Change in CHQ-PF-50 Psychological Summary score 12 M Change in (CHAQ) Disability Index score 12 M Change in (WBFPRS) 12M Change in growth velocity 12 months Serum denosumab concentration and (BTM) collected at 1,10,30,60 days after first dose of 3-M Dosing Regimen and every 3 M |
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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) * 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 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 s 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 last 12 months on 6-Month Dosing Regimen to 12 months on 3-Month Dosing Regimen - Incidence of X-ray confirmed new and worsening vertebral fractures from last 12 months on 6-Month Dosing Regimen to 12 months on 3- Month Dosing Regimen - Incidence of X-ray confirmed new vertebral fractures from last 12 months on 6-Month Dosing Regimen to 12 months on 3-Month Dosing Regimen - Subject incidence of improving vertebral fractures from baseline of 3- Month Dosing Regimen to 12 months on 3-Month Dosing Regimen - Incidence of vertebral and nonvertebral fractures from last 12 months on 6-Month - Dosing Regimen to 12 months on 3-Month Dosing Regimen (in subjects 5 years of age or older) - 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-adjusted Z-scores for height, weight and BMI) at 12 months in subjects receiving the 3-Month Dosing Regimen - Serum concentration of denosumab and serum BTM on days 1, 10, 30, 60, and every 3 months in subjects on 3-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 | 3 |
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 |
Czechia |
France |
Germany |
Hungary |
Italy |
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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An individual subject is considered to have completed the study if he/she has completed at least 12 months of 3-Month Dosing Regimen and a minimum of 36 months on study. As of 30 September 2021, due to the life-threatening risk of hypercalcemia, subjects on study who had not completed their EOS visit were immediately discontinued from IP, and will be followed for safety for 24 weeks following the last dose of IP per the updated Schedule of Assessments (Table 7-5).Please ref section 3.5.2-protcol |
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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 |