Clinical trial NCT03993821: Burosumab for CSHS
Official title: An Open Label Trial to Assess the Safety and Efficacy of Burosumab in a Single Patient With Cutaneous Skeletal Hypophosphatemia Syndrome (CSHS)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: EARLY_PHASE1
Conditions: Cutaneous Skeletal Hypophosphatemia Syndrome (CSHS)
Epidermal Nevus Syndrome
Keywords: CSHS
Cutaneous Skeletal Hypophosphatemia Syndrome
Epidermal Nevus Syndrome
Lead sponsor: Children's National Research Institute
Sponsor class: OTHER
Collaborators: name: Children's National Research Institute
name: Ultragenyx Pharmaceutical Inc
First posted: 2019-06-21
Enrollment: 1
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is an open-label, 52-week study designed to assess the efficacy, safety and pharmacodynamics (PD) of burosumab in a single subject with cutaneous skeletal hypophosphatemia syndrome (CSHS). Burosumab (formerly KRN23) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to and inhibits the activity of fibroblast growth factor 23 (FGF23), leading to an increase in serum phosphorus levels. It is hypothesized that burosumab may provide clinical benefit in this patient due to the common underlying feature in this patient and in patients with X-linked hypophosphatemia (in whom burosumab is FDA-approved) - abnormally elevated FGF23, in the context of low age-adjusted serum phosphorous levels. Patient will be seen at Screening, Baseline and every 2-4 wks, as described in "Schedule of Activities"
Primary purpose: TREATMENT

Brief summary: Burosumab (also known as the drug, Crysvita®) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to and inhibits the activity of fibroblast growth factor 23 (FGF23), leading to an increase in serum phosphorus levels. This drug is already approved for use in patients with X-linked hypophosphatemia (XLH), but not for Cutaneous Skeletal Hypophosphatemia Syndrome (CSHS). It is hypothesized that burosumab may provide clinical benefit to a patient with CSHS due to the common underlying feature in this patient and in patients with XLH - abnormally elevated FGF23 in the context of low age -adjusted serum phosphorous levels.

Detailed description: There are multiple disorders (each with a unique underlying cause) that result in unusually high circulating levels of FGF23, which in turn result in renal phosphate wasting and reduced (or aberrantly normal in relationship to elevated FGF23) levels of 1,25-dihydroxy vitamin D (1,25\[OH\]2D). Across these disorders the clinical symptoms are similar and often include osteomalacia (and, in children, rickets), muscle weakness, fatigue, bone pain, and fractures. Burosumab has been FDA-approved for one of these disorders, X-linked hypophosphatemia (XLH). In single- and repeat-dose clinical studies in subjects with XLH, subcutaneous (SC) administration of burosumab consistently increased and sustained serum phosphorus levels and tubular reabsorption of phosphate (TRP) and improved radiologic rickets, without a major impact on urine calcium levels. Positive results were also observed in a nonclinical pharmacology model of XLH. It is hypothesized that burosumab may provide clinical benefit in this patient due to the common underlying feature in this patient and in patients with XLH - abnormally elevated FGF23 in the context of low age -adjusted serum phosphorous levels.

Eligibility criteria: Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Patient has confirmed CSHS by physician diagnosis
2. Patient has confirmed FGF23 elevations in the context of a low fasting serum phosphorous \< 2.5 mg/dL
3. Patient able to tolerate burosumab treatment
4. Have a corrected serum calcium level \< 10.8 mg/dL
5. Have an eGFR \>25 mL/min/1.73m2 (using CKD-EPI equation)
6. Must be willing in the opinion of the investigators, to comply with study procedures and schedule
7. Provide written informed consent by the subject or a Legal Authorized Representative (LAR) after the study has been explained and prior to any research related procedures begin
8. Must have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study.
9. Must be willing to use a highly effective method of contraception for the duration of the study and for at least 12 weeks after the last dose of the study drug. Highly effective methods of contraception include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (e.g., oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (e.g., oral, injectable, implantable), intrauterine device (IUD) or intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, or sexual abstinence (i.e., refraining from heterosexual intercourse during the entire period of risk associated with the study treatments, when this is in line with the preferred and usual lifestyle of the subject)

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Concomitant use of active vitamin D (i.e. calcitriol) and/or exogenous phosphate supplementation during burosumab therapy. Subjects will be allowed over the counter Vitamin D should levels drop below \<20 ng/ml
2. Blood phosphorus level within or above the normal range while not taking phosphate or active Vitamin D.
3. Severe renal impairment or end-stage renal disease, defined as an eGFR of less than 25 ml/min/1.73m2
4. The use or enrollment in studies using other investigational therapies including other monoclonal antibodies
5. Subject or Legally Authorized Representative not willing or not able to give written informed consent
6. In the investigator's opinion, the subject may not be able to meet all the requirements for study participation
7. History of hypersensitivity to burosumab excipients that in the opinion of the investigator, places the subject at an increased risk of adverse effects
8. Subject has a condition that in the opinion of the investigator could present a concern for subject safety or data interpretation.

Primary outcomes:
measure: Serum Phosphorus change
timeFrame: 52 weeks
Secondary outcomes:
measure: Changes in 1,25(OH)2-Vitamin D
timeFrame: 52 weeks
measure: Changes in tubular reabsorption of phosphate (TRP)
timeFrame: 52 weeks
measure: Changes in TmP/GFR (the ratio of renal tubular maximum phosphate reabsorption rate to glomerular filtration rate
timeFrame: 52 weeks
measure: Biomechanical Marker
timeFrame: 52 weeks
measure: 6-minute walk test
timeFrame: 52 weeks
measure: Sit-to-Stand test (STST)
timeFrame: 2 weeks
measure: Brief Pain Inventory (BPI)
timeFrame: 52 weeks
measure: Brief Fatigue Inventory (BFI)
timeFrame: 52 weeks
measure: SF36 item short health survey (SF-36)
timeFrame: 52 weeks
measure: PROMIS Pain Intensity
timeFrame: 52 weeks
measure: PROMIS Pain Interference
timeFrame: 52 weeks
measure: PROMIS Physical Function with Mobility Aid
timeFrame: 52 weeks
measure: PROMIS Fatigue
timeFrame: 52 weeks
Other outcomes:
Locations:
city: Washington
country: United States
facility: Children's National Hospital
state: District of Columbia
Study officials:
affiliation: Children's National Health System
name: Laura Tosi, MD
role: PRINCIPAL_INVESTIGATOR
References: