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Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of Burosumab in Patients Less Than 1 Year of Age

Primary Purpose

X-linked Hypophosphatemia (XLH)

Status

Active

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Burosumab

About this trial

This is an interventional treatment trial for X-linked Hypophosphatemia (XLH)

Eligibility Criteria

undefined - 1 Year (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male or female pediatric subjects, aged <12 months at burosumab treatment initiation.
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.
Presenting serum phosphate levels below the age-specific LLN at Screening.
A legally authorized representative has provided written informed consent prior to any research-related procedures.
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.

Exclusion Criteria:

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.
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.
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.
Presence of nephrocalcinosis on renal ultrasound.
Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits.
Presence of a concurrent disease or condition that would interfere with study participation or affect subject safety.
Predisposition to infection or known immunodeficiency.
Severe dermatological conditions over the available injection sites.
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.
Metabolic bone disease, nutritional rickets and/or osteopenia of other origin than XLH at Screening and/or Baseline.
Serum levels of 25-hydroxyvitamin D (25(OH)D) below the LLN that are clinically significant in the opinion of the Investigator.
Evidence of any hyperparathyroidism not associated with XLH as determined by the Investigator.

Sites / Locations

Kepler Universitaetsklinikum GmbH
Centre de reference des maladies renales rares-Hospices Civils de Lyon-Hopital Femme Mere Enfant
Hopital Kremlin APHP
Ospedale Pediatrico Bambino Gesù
Hospital Virgen del Rocío
Karolinska University Hospital
Evelina London Children's Hospital - Guy's & St Thomas' NHS Foundation Trust
Great Ormond Street Hospital
Royal Manchester Children's Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment

Arm Description

Pediatric subjects > = 6 months to < 12 months will receive a starting dose of 0.4mg/kg administered subcutaneously (SC) every 2 weeks (Q2W) for 48 weeks with the option of the dose to be increased to 0.8mg/kg upon recommendation of the Data Safety Management Board (DSMB). The dose can be either increased up to a maximum of 2 mg/kg or decreased to 0.2 mg/kg depending on serum phosphate response. Upon recommendation of the DSMB subjects < 6 months can then start at 0.4mg/kg starting dose administered subcutaneously (SC) every 2 weeks (Q2W) for 48 weeks with the option to be increased to 0.8mg/kg upon recommendation of the DSMB and can be either increased up to a maximum of 2 mg/kg or decreased to 0.2 mg/kg depending on serum phosphate response.

Outcomes

Primary Outcome Measures

To assess the safety and tolerability of Burosumab in paediatric subjects with X-linked Hypophosphatemia (XLH) starting treatment below 12 months of age

Incidence, frequency, and severity of adverse events (AEs) and serious AEs (SAEs), including clinically significant changes in laboratory, physical examinations, vital signs, ECGs and imaging assessments

Secondary Outcome Measures

To characterize the pharmacokinetics (PK) of Burosumab following subcutaneous (SC) injection in paediatric subjects with XLH below 12 months of age.

Burosumab serum concentrations and PK parameters, including apparent clearance (CL/F), apparent volume of distribution (V/F), area under the serum concentration-time curve (AUC), maximum serum drug concentration (Cmax) and other parameters, as appropriate.

To characterize the effect of Burosumab on serum phosphate and 1,25-dihydroxyvitamin D (1,25[OH]2D) in paediatric subjects with XLH starting treatment below 12 months of age

Changes in serum phosphate and 1,25-dihydroxyvitamin D (1,25[OH]2D)

To assess the clinical effects of Burosumab on growth and prevention and/or healing of rickets and skeletal deformities

Change in serum alkaline phosphatase (ALP).

To assess the clinical effects of Burosumab on growth and prevention and/or healing of rickets and skeletal deformities

Appearance in radiographic appearance of rickets severity as assessed by the Radiograph Global Impression of Change (RGI-C) scoring system.

To assess the clinical effects of burosumab on growth and prevention and/or healing of rickets and skeletal deformities

The appearance in rickets severity assessed by total Rickets Severity Score (RSS).

To assess the clinical effects of burosumab on growth and prevention and/or healing of rickets and skeletal deformities

Change in lower extremity skeletal abnormalities, including genu varum and genu valgus, as determined by the RGI-C long leg score.

To assess the clinical effects of burosumab on growth and prevention and/or healing of rickets and skeletal deformities

Change in recumbent length in cm, height-for-age z-scores, and percentiles.

Full Information

NCT ID

NCT04188964

First Posted

November 25, 2019

Last Updated

October 4, 2022

Sponsor

Kyowa Kirin Pharmaceutical Development Ltd

1. Study Identification

Unique Protocol Identification Number

NCT04188964

Brief Title

Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of Burosumab in Patients Less Than 1 Year of Age

Official Title

A Phase 1/2, Open-label, Multicenter, Non-randomized Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of Burosumab in Pediatric Patients From Birth to Less Than 1 Year of Age With X-linked Hypophosphatemia (XLH)

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Active, not recruiting

Study Start Date

February 26, 2020 (Actual)

Primary Completion Date

February 2023 (Anticipated)

Study Completion Date

April 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Kyowa Kirin Pharmaceutical Development Ltd

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

A Phase 1/2, Open-label, Multicenter, Non-randomized Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of Burosumab in Paediatric Patients from Birth to Less than 1 Year of Age with X-linked Hypophosphatemia (XLH)

Detailed Description

BUR-CL207 is a multicenter, open-label, non-randomized Phase 1/2 study in pediatric patients with XLH initiating treatment with burosumab at <12 months of age. The study includes a total treatment period of up to 48 weeks across 3 cohorts. Subjects will be enrolled in 2 age subgroups: (1) ≥6 months to <12 months of age, and (2) <6 months of age at initiation of burosumab treatment. Cohorts will aim to include 3 subjects per cohort depending on the starting dose of burosumab and relative response of patients to treatment as assessed by serum phosphate levels and by the treating physician (Investigator). Cohorts will commence in a staggered manner starting with Cohort 1, followed by Cohorts 2 and 3, which may start in parallel after an adequate observation period (4 weeks) in Cohort 1 and with approval from the Sponsor's Medical Monitor and the DSMB. The cohorts are defined as follows: Cohort 1: pediatric subjects with XLH and hypophosphatemia (serum phosphate below the age-adjusted lower limit of normal [LLN]), and age from ≥6 months to <12 months of age at initiating treatment with burosumab with starting dose of 0.4 mg/kg. Cohort 2: pediatric subjects with XLH and hypophosphatemia (serum phosphate below the age-adjusted LLN), and age from ≥6 months to <12 months of age at initiating treatment with burosumab with a starting dose of 0.8 mg/kg (upon Data Safety Monitoring Board [DSMB] confirmation). Cohort 3: pediatric subjects with XLH and hypophosphatemia (serum phosphate below the age-adjusted LLN), and <6 months of age at initiating treatment with burosumab with a starting dose of 0.4 mg/kg (upon DSMB confirmation). Following enrollment of the first 3 or 4 subjects in Cohort 3, an interim population PK/PD evaluation may be performed to determine whether the starting dose for the cohort can be increased to 0.8 mg/kg.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

X-linked Hypophosphatemia (XLH)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

16 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Burosumab

Other Intervention Name(s)

KRN23, Crysvita

Intervention Description

Burosumab is a sterile clear colourless to slightly yellow and preservative free solution supplied in single use 5ml vials containing 1 mL of Burosumab at a concentration of 10mg/mL,20 mg/mL or 30mg/mL, administered by SC injections every 2 weeks.

Primary Outcome Measure Information:

Title

To assess the safety and tolerability of Burosumab in paediatric subjects with X-linked Hypophosphatemia (XLH) starting treatment below 12 months of age

Description

Time Frame

From Baseline to scheduled time points (measured throughout the study up to Week 48).

Secondary Outcome Measure Information:

Title

To characterize the pharmacokinetics (PK) of Burosumab following subcutaneous (SC) injection in paediatric subjects with XLH below 12 months of age.

Description

Time Frame

Measured throughout the study up to Week 48

Title

To characterize the effect of Burosumab on serum phosphate and 1,25-dihydroxyvitamin D (1,25[OH]2D) in paediatric subjects with XLH starting treatment below 12 months of age

Description

Changes in serum phosphate and 1,25-dihydroxyvitamin D (1,25[OH]2D)

Time Frame

Change from Baseline at Week 20, 26, 32, 40 and 48

Title

To assess the clinical effects of Burosumab on growth and prevention and/or healing of rickets and skeletal deformities

Description

Change in serum alkaline phosphatase (ALP).

Time Frame

Baseline and Week 48

Title

To assess the clinical effects of Burosumab on growth and prevention and/or healing of rickets and skeletal deformities

Description

Appearance in radiographic appearance of rickets severity as assessed by the Radiograph Global Impression of Change (RGI-C) scoring system.

Time Frame

At week 48

Title

To assess the clinical effects of burosumab on growth and prevention and/or healing of rickets and skeletal deformities

Description

The appearance in rickets severity assessed by total Rickets Severity Score (RSS).

Time Frame

At week 48

Title

To assess the clinical effects of burosumab on growth and prevention and/or healing of rickets and skeletal deformities

Description

Change in lower extremity skeletal abnormalities, including genu varum and genu valgus, as determined by the RGI-C long leg score.

Time Frame

At week 48

Title

To assess the clinical effects of burosumab on growth and prevention and/or healing of rickets and skeletal deformities

Description

Change in recumbent length in cm, height-for-age z-scores, and percentiles.

Time Frame

At week 48

10. Eligibility

Sex

All

Maximum Age & Unit of Time

1 Year

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male or female pediatric subjects, aged <12 months at burosumab treatment initiation. 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. Presenting serum phosphate levels below the age-specific LLN at Screening. A legally authorized representative has provided written informed consent prior to any research-related procedures. 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. Exclusion Criteria: 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. 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. 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. Presence of nephrocalcinosis on renal ultrasound. Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits. Presence of a concurrent disease or condition that would interfere with study participation or affect subject safety. Predisposition to infection or known immunodeficiency. Severe dermatological conditions over the available injection sites. 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. Metabolic bone disease, nutritional rickets and/or osteopenia of other origin than XLH at Screening and/or Baseline. Serum levels of 25-hydroxyvitamin D (25(OH)D) below the LLN that are clinically significant in the opinion of the Investigator. Evidence of any hyperparathyroidism not associated with XLH as determined by the Investigator.

Facility Information:

Facility Name

Kepler Universitaetsklinikum GmbH

City

Linz

Country

Austria

Facility Name

Centre de reference des maladies renales rares-Hospices Civils de Lyon-Hopital Femme Mere Enfant

City

Lyon

Country

France

Facility Name

Hopital Kremlin APHP

City

Paris

Country

France

Facility Name

Ospedale Pediatrico Bambino Gesù

City

Rome

Country

Italy

Facility Name

Hospital Virgen del Rocío

City

Sevilla

Country

Spain

Facility Name

Karolinska University Hospital

City

Stockholm

Country

Sweden

Facility Name

Evelina London Children's Hospital - Guy's & St Thomas' NHS Foundation Trust

City

London

Country

United Kingdom

Facility Name

Great Ormond Street Hospital

City

London

Country

United Kingdom

Facility Name

Royal Manchester Children's Hospital

City

Manchester

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of Burosumab in Patients Less Than 1 Year of Age

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