E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
XLH is a rare, genetic disorder that is serious, chronically debilitating and represents an unmet medical need. This genetic deficiency is estimated to occur in about 1:20,000 live births (Burnett et al. 1964), (Imel et al. 2005). XLH is the most common inherited form of rickets and the most common inherited defect in renal tubular phosphate transport. XLH is transmitted as an X-linked dominant disorder (Dixon et al. 1998). |
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E.1.1.1 | Medical condition in easily understood language |
Inheritable form of rickets |
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E.1.1.2 | Therapeutic area | Body processes [G] - Bones and nerves physological processes [G11] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10016206 |
E.1.2 | Term | Familial hypophosphataemic rickets |
E.1.2 | System Organ Class | 100000004850 |
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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 assess the safety and tolerability of burosumab in pediatric subjects with X-linked Hypophosphatemia (XLH) starting treatment below 12 months of age with up to 64 weeks of exposure. |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives: • To characterize the effect of burosumab on serum phosphate, 1,25-dihydroxyvitamin D (1,25[OH] 2 D), and other pharmacodynamic (PD) markers of phosphate homeostasis in pediatric subjects with XLH starting treatment below 12 months of age. • To characterize the pharmacokinetics (PK) of burosumab following subcutaneous (SC) injection in pediatric subjects with XLH below 12 months of age. • To assess the clinical effects of burosumab on growth and prevention and/or healing of rickets and skeletal deformities. Exploratory Objectives: • To evaluate presence and appearance of bone and skeletal XLH related abnormalities in pediatric subjects starting treatment below 12 months of age. • To evaluate anthropometric and motor development in pediatric subjects with XLH. • To characterize the immunogenicity of burosumab following administration to pediatric subjects with XLH. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Main Criteria for Inclusion: 1. Male or female pediatric subjects, aged <12 months at burosumab treatment initiation. 2. Pediatric subjects with PHEX mutation or variant of uncertain significance in either the subject or a directly related family member with appropriate X-linked inheritance. 3. Presenting serum phosphate levels below the age-specific LLN at Screening. 4. A legally authorized representative has provided written informed consent prior to any research-related procedures. 5. A legally authorized representative must, in the opinion of the Investigator, be willing and able to complete all aspects of the study, adhere to the study visit schedule, and comply with the assessments required by the study protocol, including providing access to prior medical records for the collection of historical growth, biochemical, and radiographic data and disease history
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E.4 | Principal exclusion criteria |
Main Criteria for Exclusion: 1. The pediatric subject’s legally authorized representative is unwilling or unable to stop the subject’s treatment with oral phosphate and/or pharmacologic vitamin D metabolite or analogue (e.g. calcitriol, alfacalcidol) for at least 1 week before planned treatment start and for the duration of the study. 2. Preterm pediatric patients (defined as born before 37 weeks of pregnancy) with a chronological age of <6 months. Enrolment of preterm pediatric patients with a chronological age ≥6 months must be confirmed by the Study Medical Monitor before study entry. 3. Impairment of renal function measured as serum creatinine above the age-adjusted normal range and estimated GFR (calculated using the Bedside Schwartz equation) below the age-adjusted normal range. 4. Presence of nephrocalcinosis on renal ultrasound 5. Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits. 6. Presence of a concurrent disease or condition that would interfere with study participation or affect subject safety. 7. Predisposition to infection or known immunodeficiency. 8. Severe dermatological conditions over the available injection sites. 9. Use of any investigational product or investigational medical device within 30 days prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments. 10. Nutritional rickets and/or osteopenia to include exclusion of patients with metabolic bone disease of other origin than XLH at Screening and/or Baseline. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoints: • Incidence, frequency, and severity of AEs and SAEs, including clinically significant changes in laboratory and imaging assessments, from Baseline to scheduled time points (measured throughout the study up to Week 64). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Even evaluation times to week 64/ followup week 70 |
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E.5.2 | Secondary end point(s) |
Change from Baseline over time (Week 20, 32, 40, 48, 56 and 64) in: • serum phosphate, • 1,25(OH) 2 D.
Burosumab serum concentrations and PK parameters, including CL/F, V/F, AUC, C max and other parameters, as appropriate, following SC administration.
Spot urine collection was added for measurement of calcium, creatinine, calcium/creatinine ratio, phosphate and ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) at baseline, week 2, week 6, week 20, week 48 and week 64.
Change from Baseline over time and at Week 40 and 64 in serum ALP. • Change from Baseline or from time of appearance in radiographic appearance of rickets severity as assessed by the RGI-C scoring system at Week 40 and 64. • Change from Baseline or from time of appearance in rickets severity assessed by total RSS at Week 40 and 64. • Change from Baseline in lower extremity skeletal abnormalities, including genu varum and genu valgus, as determined by the RGI-C long leg score at Week 40 and 64. • Change from Baseline in recumbent length at Week 40 and Week 64 in cm, height-for-age z- scores, and percentiles. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Change from Baseline over time (Week 20, 32, 40, 48, 56 and 64) in: • serum phosphate, • 1,25(OH) 2 D. Change from Baseline over time and at Week 40 and 64 in serum ALP. • Change from Baseline or from time of appearance in radiographic appearance of rickets severity as assessed by the RGI-C Spot urine -baseline, week 2, week 6, week 20, week 48 and week 64. scoring system at Week 40 and 64. • Change from Baseline or from time of appearance in rickets severity assessed by total RSS at Week 40 and 64. • Change from Baseline in lower extremity skeletal abnormalities, as determined by the RGI-C long leg score at Week 40 and 64. • Change from Baseline in recumbent length at Week 40 and Week 64 in cm, height-for-age z- scores, and percentiles. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
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 | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
PK in under 12 months population |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
France |
Germany |
Italy |
Sweden |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |