| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
X-linked hypophosphatemia (XLH) is a disorder of renal phosphate wasting, and the most common heritable form of rickets. In XLH patients, high circulating levels of fibroblast growth factor 23 (FGF23) impair normal phosphate reabsorption in the kidney. Low serum phosphorus levels result in hypomineralization of bone and associated abnormalities including rickets, bowing of the legs, and short stature.
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| E.1.1.1 | Medical condition in easily understood language |
| Inheritable form of rickets |
|
| 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 |
|
| 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 |
| • Evaluate the effect of KRN23 therapy in improving rickets in children with XLH compared with active control (oral phosphate/active vitamin D) |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Efficacy Objectives:
Evaluate the effects of KRN23 as compared with active control on:
• Growth velocity and lower extremity deformity
• Pharmacodynamic markers that reflect the status of phosphorus homeostasis, including serum 1,25(OH) 2 D, serum and urinary phosphorus, ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR), and tubular reabsorption of phosphate (TRP)
• Biochemical markers of bone turnover that reflect rickets severity (alkaline phosphatase [ALP])
• Walking ability and patient-/parent-reported pain, fatigue, and physical function/mobility
Pharmacokinetic Objective:
Assess the PK of KRN23 throughout the dosing cycle
Safety Objective:
Evaluate the safety and tolerability profile of KRN23 in the treatment of children with XLH (aged 1 to ≤12 years), including adverse events (AEs) (e.g., nephrocalcinosis), as compared with active control, and immunogenicity profile |
|
| 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 to ≤12 years with radiographic evidence of rickets with a minimum rickets severity score (RSS) total score of 2 as determined by central read
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: Serum phosphorus <3.0 mg/dL (0.97 mmol/L)
4) Serum creatinine within age-adjusted normal range*
5) Serum 25(OH)D above the lower limit of normal (≥16 ng/mL) at the Screening Visit**
6) Have received both oral phosphate and active vitamin D therapy for ≥ 12 consecutive months (for children ≥3 years of age) or ≥ 6 consecutive months (for children <3 years of age) 7 days prior to the Screening Visit" (Synopsis [Diagnosis and Criteria of Inclusion and Exclusion].
7) Willing to provide access to prior medical records for the collection of historical growth and radiographic data and disease history.
8) Provide written or verbal assent (as appropriate for the subject and region) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures.
9) 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.
10) Females who have reached menarche must have a negative pregnancy test at Screening and undergo additional pregnancy testing during the study. Female subjects of childbearing potential must be willing to use a highly effective method of contraception for the duration of the study. Fertile male subjects with female partners of childbearing potential must consent to use a condom with spermicide or a highly effective method of contraception for the duration of the study plus 12 weeks after stopping the study drug. |
|
| E.4 | Principal exclusion criteria |
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the
study:
1) Tanner stage 4 or higher is assessed through physical examination in any of the following: genitals, breast, or public hair (Synopsis [Diagnosis and Criteria for Inclusion and Exclusion].
2) Height percentile >50% based on country-specific norms
3) Use of aluminum hydroxide antacids (e.g. Maalox® and Mylanta®), systemic corticosteroids, acetazolamide, and thiazides within 7 days prior to the Screening Visit
4) Current or prior use of leuprorelin (e.g., Lupron®, Viadur®, Eligard®), triptorelin (TRELSTAR®), goserelin (Zoladex®), or other drugs known to
delay puberty
5) Use of growth hormone therapy within 12 months before the Screening Visit
6) 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
7) Planned or recommended orthopedic surgery (implantation or removal), including staples, 8-plates osteotomy or any other hardware, within first 40 weeks of the study (Synopsis [Diagnosis and Criteria for Inclusion and Exclusion].
8) Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits*
9) Evidence of hyperparathyroidism (parathyroid hormone [PTH] levels 2.5X upper limit of normal [ULN])
10) Use of medication to suppress PTH (e.g., cinacalcet, calcimimetics) within 2 months prior to the Screening Visit
11) 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.
12) Presence of a concurrent disease or condition that would interfere with study participation or affect safety
13) History of recurrent infection or predisposition to infection, or of known immunodeficiency
14) Use of a therapeutic monoclonal antibody within 90 days prior to the Screening Visit or history of allergic or anaphylactic reactions to any monoclonal antibody
15) Presence or history of any hypersensitivity to KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects
16) 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 OR, in Japan, use of any investigational product or investigational medical device within 4 months prior to screening, or requirement for any investigational agent prior to completion
of all scheduled study assessments.
* Criteria to be determined based on overnight fasting (min. 4 hours) values collected at the
Screening and/or Baseline Visit
** If 25(OH)D levels are below the normal range, 25(OH)D supplementation will be prescribed.
Assuming a subject meets all other eligibility requirements, the subject may be rescreened after a minimum of 7 days of treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint will be compared between the KRN23 and active control groups:
• Change in rickets at Week 40 as assessed by the RGI-C global score |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| week 40. Long-term Assessments in Treatment Extension Period: At week 88, 112, and 140, efficacy, safety, pharmacokinetics, and exploratory assessments will be conducted as noted in the Schedule of Events |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
The following secondary endpoints will be compared between the KRN23 and active control groups:
• Proportion of subjects with a mean RGI-C global score ≥+2.0 (substantial healing) at Week 40 and
Week 64
• Change in rickets at Week 64 as assessed by the 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 assessed by the RGI-C long leg score at Weeks 40 and 64
• Change in standing height (or recumbent length in children <2 years) from baseline to Weeks 24, 40, and 64 in cm
• Change in height-for-age z-scores from baseline to Weeks 24, 40, 64
• Change in growth velocity from pre-treatment and post-treatment at Weeks 40 and 64 in cm/yr
• Pharmacodynamic* assessments including
o Change from baseline over time in serum phosphorus
o Change from baseline over time in serum 1,25(OH) 2 D, urinary phosphorus, ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR), and tubular reabsorption of phosphate (TRP)
o Change and percent change from baseline over time in biochemical markers of bone turnover that reflects rickets severity (alkaline phosphatase [ALP])
* Blood and urine to be collected after a minimum overnight fasting time of 4 hours and prior to drug administration (if applicable) per dosing regimen
• Pain, fatigue and physical function: Change from baseline in the PROMIS (Patient-Reported Outcomes Measurement Information System) Pediatric Pain Interference, Physical Function Mobility and Fatigue domain scores (for subjects ≥ 5 years of age at the Screening Visit) at Weeks 24, 40 and 64
• Pain intensity: Change from baseline in the Faces Pain Scale- Revised (FPS-R) (for subjects ≥ 5 years of age at the Screening Visit) at Weeks 24, 40 and 64
• Walking ability: Change from baseline in the Six Minute Walk Test (6MWT) total distance and percent of predicted normal (for subjects ≥ 5 years of age at the Screening Visit) at Weeks 24, 40, and 64
Pharmacokinetic:
• Serum KRN23 (pre-dose level)
Safety Assessments:
Safety will be evaluated and compared with active control by the incidence, frequency, and severity of AEs and serious adverse events (SAEs), including clinically significant changes from baseline to
scheduled time points for the following variables:
• Vital signs and weight
• Physical examinations
• eGFR (calculated using the Bedside Schwartz equation)
• Renal ultrasound to evaluate nephrocalcinosis
• Echocardiogram (ECHO) (for subjects ≥ 5 years of age)
• Chemistry, hematology, and urinalysis, including additional KRN23/XLH biochemical parameters of interest (serum 25(OH)D; lipase; amylase; creatinine; serum calcium and iPTH, and urinarycalcium and creatinine)
• Anti-KRN23 antibody testing and dose-limiting toxicities
• Concomitant medications
• ECG
Exploratory Assessments:
• Health-related quality of life: Change from baseline in the SF-10 for Children Health Survey (SF-10; for subjects ≥ 5 years of age at the Screening Visit) at Weeks 24, 40, and 64
• Dental evaluation to assess the number of dental events such as dental caries, delay in eruption of the dentition, enamel hypoplasia, dental abscesses, and gingivitis
Data Monitoring Committee
An independent DMC that includes members with expertise in metabolic bone disease, cardiology, and nephrology, and the conduct of clinical trials in children will act in an advisory capacity to
monitor subject safety on a routine basis throughout the trial. The DMC will meet at least twice a year during the active-controlled period. The roles and responsibilities of the DMC will be defined in the
DMC Charter. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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) | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| comparators - Standard of care |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 |
| France |
| Germany |
| Ireland |
| Italy |
| Japan |
| Korea, Republic of |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| 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
|
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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