Clinical trial NCT02304367: Study of Burosumab (KRN23) in Adults With Tumor-Induced Osteomalacia (TIO) or Epidermal Nevus Syndrome (ENS)
Official title: A Phase 2 Open-Label Trial to Assess the Efficacy and Safety of KRN23, an Antibody to FGF23, in Subjects With Tumor-Induced Osteomalacia (TIO) or Epidermal Nevus Syndrome (ENS)-Associated Osteomalacia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tumor Induced Osteomalacia (TIO)
Epidermal Nevus Syndrome (ENS)
Keywords: TIO
ENS
FGF23
KRN23
Lead sponsor: Kyowa Kirin Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2014-12-01
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary objectives of this study are to evaluate the effect of burosumab treatment on:

* Increasing serum phosphorus levels in adults with TIO or ENS-associated osteomalacia
* Improvement in TIO/ENS-associated osteomalacia as determined by osteoid thickness (O.Th), osteoid surface/bone surface (OS/BS), osteoid volume/bone volume (OV/BV) and mineralization lag time (MLt).


Eligibility criteria: Inclusion Criteria:

1. Have a clinical diagnosis of TIO/ENS-associated osteomalacia based on evidence of excessive fibroblast growth factor 23 (FGF23) that was not amenable to cure by surgical excision of the underlying tumor/lesion (documented by Investigator).
2. Be ≥ 18 years of age
3. Have a fasting serum phosphorus level \< 2.5 mg/dL
4. Have an FGF23 level ≥ 100 pg/mL by Kainos assay
5. Have a ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) \< 2.5 mg/dL
6. Have an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (using Cockcroft-Gault formula). Subjects with eGFR ≥ 30 but \< 60 mL/min will be considered eligible as long as in the opinion of the investigator the decline in renal function is not related to nephrocalcinosis.
7. Have a corrected serum calcium level \< 10.8 mg/dL
8. Females of child-bearing potential must have a negative urine pregnancy test at Screening and Baseline and be willing to have additional pregnancy tests during the study. Females considered not to be of childbearing potential include those who have not experienced menarche, are post-menopausal (defined as having no menses for at least 12 months without an alternative medical cause) or are permanently sterile due to total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy.
9. Be willing to use 2 forms of effective methods of contraception while participating in the study (sexually active subjects) and for 12 weeks after last dose of study drug.
10. Be willing to provide access to prior medical records to determine eligibility including imaging, biochemical, and diagnostic, medical, and surgical history data
11. Provide written informed consent after the nature of the study has been explained, and prior to any research-related procedures
12. Be willing and able to complete all aspects of the study, adhere to the study visit schedule and comply with the assessments (in the opinion of the investigator)

Exclusion Criteria:

1. Have a prior diagnosis of human immunodeficiency virus (HIV), hepatitis B and/or hepatitis C
2. Have a history of recurrent infection, a predisposition to infection, or a known immunodeficiency
3. Are pregnant or breastfeeding at Screening or are planning to become pregnant (self or partner) at any time during the study
4. Have participated in an investigational drug or device trial within 30 days prior to Screening or are currently enrolled in another study of an investigational product or device
5. Have used a therapeutic monoclonal antibody (mAb), including KRN23, within 90 days prior to Screening or have a history of allergic or anaphylactic reactions to any mAb
6. Have or a have a history of any hypersensitivity to KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects
7. Have used a pharmacologic vitamin D metabolite or its analog (e.g., calcitriol, doxercalciferol, and paricalcitol), phosphate, or aluminum hydroxide antacids (e.g., Maalox® and Mylanta®) within 2 weeks prior to Screening or during the study
8. Have used medication to suppress parathyroid hormone (PTH) (e.g., Sensipar®, cinacalcet, calcimimetics) within 2 months prior to Screening
9. Have a history of malignancy within 5 years of study entry with the exception of phosphaturic mesenchymal tumors (PMTs) of the mixed connective tissue type or non-melanoma skin cancers such as basal cell skin cancer
10. Have donated blood or blood products within 60 days prior to Screening
11. Have a history of allergic reaction to or have shown adverse reactions to a tetracycline (e.g., tetracycline hydrochloride \[HCl\] and demeclocycline), benzodiazepines, fentanyl or lidocaine
12. Have any condition, which in the opinion of the investigator and sponsor, could present a concern for either subject safety or difficulty with data interpretation

Primary outcomes:
measure: Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the Mid-Point of the Dose Intervals Between Baseline and Week 24
timeFrame: Mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22 [there was no study visit at Week 18])
measure: Change From Baseline to Week 48 in Osteoid Thickness
timeFrame: Baseline, Week 48
measure: Change From Baseline to Week 48 in Osteoid Surface/Bone Surface (OS/BS)
timeFrame: Baseline, Week 48
measure: Change From Baseline to Week 48 in Osteoid Volume/Bone Volume (OV/BV)
timeFrame: Baseline, Week 48
measure: Change From Baseline to Week 48 in Mineralization Lag Time (MLt)
timeFrame: Baseline, Week 48
Secondary outcomes:
measure: Percentage of Participants Achieving Mean Serum Phosphorus Levels Above 2.5 mg/dL at the End of the Dose Intervals Between Baseline and Week 24
timeFrame: End of each dose interval from Baseline to Week 24 (Weeks 4, 8, 12, 16, 20, and 24)
measure: Mean Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24
timeFrame: Baseline and the mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22)
measure: Percent Change From Baseline in Serum Phosphorus Levels at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24
timeFrame: Baseline and the mid-point of each dose interval from Baseline to Week 24 (Weeks 2, 6, 10, 14 and 22)
measure: Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, and 24
measure: Percent Mean Change From Baseline in Serum Phosphorus Levels at the End of the Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24
timeFrame: Baseline and Weeks 4, 8, 12, 16, 20, and 24
measure: Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Levels Between Baseline and Week 24
timeFrame: Pre-dose on Day 1 and at Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 21, 22, and 24
measure: Change From Baseline Over Time in Serum 1,25-dihydroxyvitamin D (1,25(OH)2D) Concentration
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Total Serum Fibroblast Growth Factor 23 (FGF23) Concentration
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Free Serum Fibroblast Growth Factor 23 (FGF23) Concentration
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in 24-hour Urinary Phosphorus
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Tubular Reabsorption of Phosphate (TRP)
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Ratio of Renal Tubular Maximum Phosphate Reabsorption Rate to Glomerular Filtration Rate (TmP/GFR)
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Fractional Excretion of Phosphorus (FEP)
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Serum Alkaline Phosphatase (ALP)
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Bone-Specific Alkaline Phosphatase (BALP)
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Percent Change From Baseline Over Time in BALP
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Carboxy Terminal Cross-Linked Telopeptide of Type 1 Collagen (CTx)
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Percent Change From Baseline Over Time in CTx
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Procollagen Type 1 N-Propeptide (P1NP)
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Percent Change From Baseline Over Time in P1NP
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Osteocalcin
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Percent Change From Baseline Over Time in Osteocalcin
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Elbow Measurements
timeFrame: Baseline and Weeks 24 and 48
measure: Change From Baseline Over Time in Hand-Held Dynamometry (HHD) Knee Measurements
timeFrame: Baseline and Weeks 24 and 48
measure: Change From Baseline Over Time in Sit-to-Stand (STS) Test
timeFrame: Baseline and Weeks 24 and 48
measure: Change From Baseline Over Time in Weighted Arm Lift (WAL) Test
timeFrame: Baseline and Weeks 24 and 48
measure: Change From Baseline Over Time in Six-Minute Walk Test (6MWT)
timeFrame: Baseline and Weeks 24 and 48
measure: Change From Baseline Over Time in Brief Pain Inventory (BPI) Worst Pain Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Severity Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Brief Pain Inventory (BPI) Pain Interference Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Worst Fatigue Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Severity Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Fatigue Interference Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in Brief Fatigue Inventory (BFI) Global Fatigue Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Component Summary Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Physical Functioning Domain Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Physical Domain Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Bodily Pain Domain Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) General Health Perceptions Domain Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Component Summary Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Vitality Domain Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Social Functioning Domain Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Role Emotional Domain Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
measure: Change From Baseline Over Time in 36-Item Short Form Health Survey (SF-36) Mental Health Domain Score
timeFrame: Baseline and Weeks 24, 48, 96, 144, 168, 192, 216, and 240
Other outcomes:
measure: Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation
timeFrame: From first dose of study drug up to database lock date (July 07, 2021); median duration of treatment in the TIO analysis set was 1594.0 (range: 168-2106) days.
measure: Number of Participants With Anti-burosumab Antibodies
timeFrame: From first dose of study drug up to database lock date (July 07, 2021); median duration of treatment in the TIO analysis set was 1594.0 (range: 168-2106) days.
Locations:
city: Golden
country: United States
facility: Colorado Center for Bone Research at Panorama Orthopedics and Spine Center
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Indianapolis
country: United States
facility: Indiana University Hospital
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Houston
country: United States
facility: Houston Methodist Research Institute
state: Texas
Study officials:
affiliation: Ultragenyx Pharmaceutical Inc
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Khadora M, Mughal MZ. Burosumab treatment in a child with cutaneous skeletal hypophosphatemia syndrome: A case report. Bone Rep. 2021 Oct 1;15:101138. doi: 10.1016/j.bonr.2021.101138. eCollection 2021 Dec.