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

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ClinicalTrials.gov Identifier: NCT04188964
Recruitment Status : Recruiting
First Posted : December 6, 2019
Last Update Posted : July 13, 2020
Sponsor:
Information provided by (Responsible Party):
Kyowa Kirin Pharmaceutical Development Ltd

Brief Summary:

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)


Condition or disease Intervention/treatment Phase
X-linked Hypophosphatemia (XLH) Drug: Burosumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : February 26, 2020
Estimated Primary Completion Date : February 2023
Estimated Study Completion Date : April 2024


Arm Intervention/treatment
Experimental: Treatment
Pediatric subjects > = 6 months to < 12 months will receive a starting dose of 0.4mg/kg administered subcutaneously (SC) every 2 weeks (Q2W) for 64 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 64 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.
Drug: Burosumab
Burosumab is a sterile clear colourless 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
Other Names:
  • KRN23
  • Crysvita




Primary Outcome Measures :
  1. Safety and tolerability of burosumab will be measured in subjects with XLH starting treatment below 12 months of age by studying the number, severity and relatedness of Adverse Events (including laboratory and imaging assessments). [ Time Frame: From baseline, measured throughout the study up to Week 64. ]
    Incidence, frequency, and severity of AEs and SAEs, including clinically significant changes in laboratory assessments as well as ECHO, ECG, ultrasound and X-Ray images.


Secondary Outcome Measures :
  1. The number of participants showing an effect of burosumab on pharmacodynamic (PD) markers of phosphate homeostasis. [ Time Frame: Baseline, (Week 20, 32, 40, 48, 56 and 64). ]
    Number of participants with changes in serum phosphate and 1,25(OH)2D.

  2. To characterize the pharmacokinetics (PK) of burosumab following subcutaneous (SC) injection. [ Time Frame: Baseline, (Day 3, 7, 11, and 14, Week 4, 6, 8, 12, 16, 40, 64) ]
    Burosumab serum concentrations and PK parameters.

  3. The number of participants with change in serum ALP showing clinical effects of burosumab on growth and prevention and/or healing of rickets and skeletal deformities. [ Time Frame: Baseline, Week 40 and 64. ]
    Change in serum ALP.

  4. Growth and prevention and/or healing of rickets and skeletal deformities will be measured by comparing radiographs taken at baseline to x rays at the following timepoints: [ Time Frame: Baseline, Week 40 and 64. ]
    Change in time of appearance in radiographic appearance of rickets severity as assessed by the RGI-C scoring system a seven-point scale (-3=severe worsening, 0=no change; +3=near/complete healing),

  5. Appearance in rickets severity assessed by total rickets severity score (RSS) [ Time Frame: Baseline, Week 40 and 64. ]
    Change in appearance in rickets severity assessed by total rickets severity score (RSS) a 10-point radiographic scoring method where 10 represents the most extreme degree of rickets severity and 0 represents the absence of radiographic changes of rickets.

  6. Lower extremity skeletal abnormalities, determined by the radiographic global impression of change (RGI-C) long leg score including genu varum and genu valgus, as determined by the RGI-C long leg score at Week 40 and 64. [ Time Frame: Baseline, Week 40 and 64. ]
    Change in lower extremity skeletal abnormalities, including genu varum and genu valgus, as determined by the RGI-C long leg scale score ranging from -3 (very much worse, or severe worsening of rickets) to +3 (very much better, or complete or near complete healing of rickets)

  7. The number of participants with change in recumbent length. [ Time Frame: Baseline, at Week 40 and Week 64 ]
    Change in recumbent length measured in centimetres to calculate height-for age z scores, and percentiles



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Ages Eligible for Study:   up to 1 Year   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  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.

Exclusion Criteria:

  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. Metabolic bone disease, nutritional rickets and/or osteopenia of other origin than XLH at Screening and/or Baseline.
  11. Serum levels of 25-hydroxyvitamin D (25(OH)D) below the LLN that are clinically significant in the opinion of the Investigator.
  12. Evidence of any hyperparathyroidism not associated with XLH as determined by the Investigator.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04188964


Contacts
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Contact: Development Division Project Management Department 609-919-1100 kkd.clintrial.82@kyowakirin.com

Locations
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France
Centre de reference des maladies renales rares-Hospices Civils de Lyon-Hopital Femme Mere Enfant Recruiting
Lyon, France
Contact: Justine Bacchetta, Prof         
Hopital Kremlin APHP Recruiting
Paris, France
Contact: Agnes Linglart, Prof         
Sponsors and Collaborators
Kyowa Kirin Pharmaceutical Development Ltd
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Responsible Party: Kyowa Kirin Pharmaceutical Development Ltd
ClinicalTrials.gov Identifier: NCT04188964    
Other Study ID Numbers: BUR-CL207
First Posted: December 6, 2019    Key Record Dates
Last Update Posted: July 13, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Familial Hypophosphatemic Rickets
Hypophosphatemia
Phosphorus Metabolism Disorders
Metabolic Diseases
Rickets, Hypophosphatemic
Rickets
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Hypophosphatemia, Familial
Renal Tubular Transport, Inborn Errors
Kidney Diseases
Urologic Diseases
Metal Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Calcium Metabolism Disorders
Vitamin D Deficiency
Avitaminosis
Deficiency Diseases
Malnutrition
Nutrition Disorders