E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
XLH is a disorder of hypophosphatemia, renal phosphate wasting, and the most common inheritable form of rickets. In XLH patients, excess circulating fibroblast growth factor (FGF23) impair phosphate reabsorption in the kidney. Chronic low serum phosphorus levels lead to defective bone mineralization and, consequently, to rickets in children and osteomalacia in adults, the two major pathologic outcomes of the hypophosphatemia. |
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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 |
The primary objectives of the study are to: • Establish the safety profile of KRN23 for the treatment of XLH in children between 1 and 4 years old • Determine the pharmacodynamic (PD) effects of KRN23 treatment on serum phosphorus and other PD markers that reflect the status of phosphate homeostasis in children between 1 and 4 years old with XLH |
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E.2.2 | Secondary objectives of the trial |
Additional study objectives are to assess the following in children between 1 and 4 years old with XLH • Effects of KRN23 on rickets • Effects of KRN23 on growth and lower extremity deformity • KRN23 drug concentration levels (PK) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Individuals eligible to participate in this study must meet all of the following criteria: 1) Male or female, aged ≥1 year and < 5 years 2) PHEX mutation or variant of uncertain significance in either the patient or in a directly related family member with appropriate X-linked inheritance 3) Biochemical findings associated with XLH including: a. Serum phosphorus < 3.0 mg/dL (0.97 mmol/L)* b. Serum creatinine within age-adjusted normal range* 4) Radiographic evidence of rickets; at least 5 subjects will be required to have a rickets severity score (RSS) at the knee of at least 1.5 points as determined by central read 5) Willing to provide access to prior medical records for the collection of historical growth, biochemical, and radiographic data and disease history 6) Provide written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures 7) 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 * Criteria to be determined based on fasting (min. 4 hours) values collected at Baseline |
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E.4 | Principal exclusion criteria |
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 1) Unwilling to stop treatment with oral phosphate and/or pharmacologic vitamin D metabolite or analog (e.g. calcitriol, alfacalcidol) during the screening period and for the duration of the study 2) Presence of nephrocalcinosis on renal ultrasound grade 4 based on the following scale: 0 = Normal 1 = Faint hyperechogenic rim around the medullary pyramids 2 = More intense echogenic rim with echoes faintly filling the entire pyramid 3 = Uniformly intense echoes throughout the pyramid 4 = Stone formation: solitary focus of echoes at the tip of the pyramid 3) Planned or recommended orthopedic surgery including staples, 8-plates or osteotomy, within the clinical trial period 4) Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits* 5) Presence or history of any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or of not completing the study 6) Presence of a concurrent disease or condition that would interfere with study participation or affect safety 7) History of recurrent infection or predisposition to infection, or of known immunodeficiency 8) 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 * Criteria to be determined based on fasting (min. 4 hours) values collected at Baseline |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety: Safety will be evaluated by the incidence, frequency and severity of adverse events (AEs) and serious adverse events (SAEs), including clinically significant changes in laboratory test results from baseline to scheduled time points. General Safety Variables will include the following: • Vital signs and weight • Physical examinations • Glomerular filtration rate (GFR) • Chemistry, hematology, and urinalysis, including additional KRN23/XLH biochemical parameters of interest (serum calcium, intact parathyroid hormone [iPTH], 25-hydroxyvitamin D [25(OH)D], amylase, lipase, and creatinine; and urinary calcium and creatinine) • Anti-KRN23 antibody testing and dose-limiting toxicities • Concomitant medications • Electrocardiogram (ECG) Ectopic Mineralization Safety Assessments include: • Renal ultrasound
Pharmacodynamics: The primary efficacy endpoint is the change from baseline over time in serum phosphorus. Additional pharmacodynamics assessments include: • Change from baseline over time in serum 1,25(OH)2D and urinary phosphorus |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week -6 to Baseline, Baseline, Week 1, every two weeks from Week 2 to 64 |
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E.5.2 | Secondary end point(s) |
• Change in rickets at Week 40 as assessed by the Radiograph Global Impression of Change (RGI C) global score • Change in rickets at Week 64 as assessed by RGI-C global score • Change from baseline in RSS total score at Weeks 40 and 64 • Change in lower extremity skeletal abnormalities, including genu varum and genu valgus, as determined by the RGI-C long leg score at Weeks 40 and 64 • Change in recumbent length/standing height from baseline to post-treatment study time points in cm, height-for-age z-scores, and percentiles. Historical growth records may be used to evaluate change in growth velocity • Change and percent change from baseline over time in serum alkaline phosphatase (ALP) • Serum KRN23 concentrations at indicated study time points |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week -6 to Baseline, Baseline, Week 1, every two weeks from Week 2 to 64 |
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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 | 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) | 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) | 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 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
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.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |