Clinical trial NCT04842032: Study to Assess the Safety, Pharmacokinetics and Efficacy of KRN23 in Pediatric Chinese Patients With XLH
Official title: An Open-label, Multi-center, Single-cohort, Post-marketing Phase 4 Study to Evaluate the Efficacy, Pharmacodynamics, and Safety of the Anti-FGF23 Antibody, KRN23, in Pediatric Chinese Patients With X-linked Hypophosphatemic Rickets/Osteomalacia (XLH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: X-linked Hypophosphatemia (XLH)
Lead sponsor: Kyowa Kirin Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2021-04-12
Enrollment: 28
Sex: ALL
Minimum age (years): 1
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the safety, pharmacokinetics and efficacy of KRN23 in pediatric Chinese patients with XLH


Eligibility criteria: Inclusion Criteria:

1. Male or female Chinese patients, aged 1 to ≤12 years at ICF signature with radiographic evidence of rickets
2. Diagnosis of XLH supported by either of the following:

   * Confirmed PHEX mutation (prior to the study with historic record) in the patient or a directly related family member with approximate X linked inheritance
   * Serum intact FGF23 level ≥30 pg/mL by Kainos assay at Screening
3. Able to receive conventional therapy (oral phosphate and pharmacologic vitamin D)
4. Biochemical findings associated with XLH: Serum phosphorus \<3.0 mg/dL (0.97 mmol/L). Serum phosphorus may be re tested (once only) at least 7 days after discontinuation of therapy, if applicable (\[see Section 3.1\])
5. Serum creatinine within age-adjusted normal range (based on overnight fasting \[minimum 4 hours\] values collected at Screening)
6. Serum 25(OH)D above or equal to the lower limit of normal (≥16 ng/mL) at Screening. If 25(OH)D levels are below the normal range, 25(OH)D supplementation will be prescribed. Assuming a patient meets all other eligibility requirements, the patient may be re tested for serum 25(OH)D after a minimum of 7 days of treatment
7. Willing to provide access to prior medical records for the collection of historical growth and radiographic data and disease history
8. Written or verbal assent (as appropriate for the patient and region) by the patient and written informed consent by legally authorized representatives provided after the nature of the study has been explained, and prior to any research-related procedures
9. Be willing and able to complete all aspects of the study, adhere to the study visit schedule and comply with the assessments, as judged by the investigator or subinvestigator
10. Female patients who have reached menarche must have a negative pregnancy test at Screening and be willing to have additional pregnancy testing during the study. If sexually active, male and female patients must be willing to use an effective method of contraception for the duration of the study and for 12 weeks after the last dose of IP

Exclusion Criteria:

1. Positive for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen (HBsAg), and/or hepatitis C virus (HCV) antibody at Screening
2. Tanner stage 4 or higher through physical examination
3. Height percentile \>50% based on country specific norms
4. Use of a pharmacologic vitamin D, its metabolites, or analogs, oral phosphate for treatment of XLH, aluminum hydroxide antacids, acetazolamide, thiazide diuretics, and/or systemic corticosteroids within 7 days prior to Week -14
5. Current or prior use of leuprorelin, triptorelin, goserelin, or other drugs known to delay puberty
6. Use of growth hormone therapy within 12 months before ICF signature
7. Have uncontrolled diabetes mellitus, defined as glycated hemoglobin (HbA1c) \>8.5% at Screening
8. Presence of nephrocalcinosis on renal ultrasound Grade 4 based on the following scale:
9. Planned or recommended orthopedic surgery (implantation or removal), including staples, 8 plates, or osteotomy, within the first 40 weeks of the study
10. Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age adjusted normal limits (based on overnight fasting \[minimum 4 hours\] values collected at the Screening)
11. Evidence of hyperparathyroidism (parathyroid hormone \[PTH\] levels 2.5 × ULN)
12. Use of medication to suppress PTH (e.g., Sensipar®, cinacalcet, calcimimetics) within 2 months prior to ICF signature
13. Presence or history of any condition that, in the view of the investigator or subinvestigator, places the subject at high risk of poor treatment compliance or of not completing the study
14. Presence of a concurrent disease or condition that would interfere with study participation or affect safety
15. History of recurrent infection or predisposition to infection, or of known immunodeficiency
16. Use of therapeutic mAb within 90 days prior to ICF signature or history of allergic or anaphylactic reactions to any mAb
17. Presence or history of any hypersensitivity to KRN23 excipients that, in the judgment of the investigator or subinvestigator, places the patient at increased risk for adverse effects
18. Use of any investigational product or investigational medical device within 30 days prior to ICF signature, or need for the use of any investigational agent prior to completion of all scheduled study assessments
19. Other patients who are considered to be ineligible for the study by the investigator or subinvestigator for reasons other than the above

Primary outcomes:
measure: Change from Baseline (CFB) in mean serum phosphorus level at the end of the dose cycle
timeFrame: Weeks 2, 4, 8, 12, 16, 24, 32, 40, 52, and 64
Secondary outcomes:
measure: Change in rickets at Weeks 40 and 64 as examined by the Radiograph Global Impression of Change (RGI-C) global score
timeFrame: Weeks 40 and 64
measure: Change in Rickets Severity Score (RSS) total score at Weeks 40 and 64
timeFrame: Weeks 40 and 64
measure: 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
timeFrame: Weeks 40 and 64
measure: Change in serum phosphorus over time
timeFrame: Weeks 0, 1, 2, 4, 8, 12, 16, 24, 32, 40, 52, 64, and 74
measure: Change in serum 1,25-dihydroxyvitamin D (1,25(OH)2D) over time
timeFrame: Weeks 0, 1, 2, 4, 8, 12, 16, 24, 32, 40, 52, 64, and 74
measure: Change in alkaline phosphatase (ALP) over time
timeFrame: Weeks 0, 1, 2, 4, 8, 12, 16, 24, 32, 40, 52, 64, and 74
measure: Change in urinary phosphorus over time
timeFrame: Weeks 0, 1, 2, 4, 8, 12, 16, 24, 32, 40, 52, 64, and 74
measure: Change in ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR; algorithm method) over time
timeFrame: Weeks 0, 1, 2, 4, 8, 12, 16, 24, 32, 40, 52, 64, and 74
measure: Change in recumbent length/standing height in cm, height for age z scores
timeFrame: Weeks 0, 24, 40 and 64
measure: Change in growth velocity from pre-treatment and post-treatment over time
timeFrame: Weeks 0, 24, 40 and 64
measure: Change in growth velocity z scores from pre-treatment and post-treatment over time
timeFrame: Weeks 0, 24, 40 and 64
measure: Six-minute walking test (6MWT) results to examine walking ability (total distance; patients ≥5 years at the time of signing the ICF only)
timeFrame: Weeks 0, 24, 40 and 64
measure: Six-minute walking test (6MWT) results to examine walking ability (percent of predicted normal; patients ≥5 years at the time of signing the ICF only)
timeFrame: Weeks 0, 24, 40 and 64
measure: Ten-item Short Form Health Survey for Children (SF-10) physical domain scores to examine health-related Quality of Life
timeFrame: Weeks 0, 24, 40 and 64
measure: Ten-item Short Form Health Survey for Children (SF-10) Psychosocial scores to examine health-related Quality of Life
timeFrame: Weeks 0, 24, 40 and 64
measure: Face Pain Scale-Revised (FPS-R) scores to examine health-related Quality of Life
timeFrame: Weeks 0, 24, 40 and 64
measure: Patient-Reported Outcomes Measurement Information System (PROMIS) scores to examine health-related Quality of Life
timeFrame: Weeks 0, 24, 40 and 64
Other outcomes:
measure: Safety of KRN23 by studying the number, severity and relatedness of Adverse Events (including laboratory and imaging assessments)
timeFrame: Week 0 to Week 76
measure: Pharmacokinetics (PK): KRN23 concentrations
timeFrame: Weeks 0, 1, 2, 4, 8, 16, 24, 40, 64, and 74
measure: Change from Week -14 to Baseline in serum phosphorus over time during Run-in Period
timeFrame: Week -14, -10 and -4
measure: Change from Week -14 to Baseline in serum 1,25(OH)2D over time during Run-in Period
timeFrame: Week -14, -10 and -4
measure: Change from Week -14 to Baseline in plasma iPTH over time during Run-in Period
timeFrame: Week -14, -10 and -4
measure: Change from Week -14 to Baseline in serum calcium over time during Run-in Period
timeFrame: Week -14, -10 and -4
measure: Change from Week -14 to Baseline in urinary phosphorus over time during Run-in Period
timeFrame: Week -14, -10 and -4
measure: Change from Week -14 to Baseline in TmP/GFR (algorithm method) over time during Run-in Period
timeFrame: Week -14, -10 and -4
measure: Safety of conventional therapy by studying the number, severity and relatedness of Adverse Events
timeFrame: Week -14 to Week 0
Locations:
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Guangzhou
country: China
facility: Guangzhou Women and Children Medical Center
city: Shanghai
country: China
facility: Shanghai 6th Hospital
city: Shanghai
country: China
facility: Shanghai Xinhua Hopsital
city: Wuhan
country: China
facility: Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology
Study officials:
affiliation: Kyowa Kirin Co., Ltd.
name: KRN23 Study Director
role: STUDY_DIRECTOR
References: