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A Trial to Assess the Safety and Efficacy of KRN23 in Epidermal Nevus Syndrome (ENS) (ENS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04320316
Recruitment Status : Active, not recruiting
First Posted : March 25, 2020
Last Update Posted : August 14, 2020
Sponsor:
Collaborator:
Ultragenyx Pharmaceutical Inc
Information provided by (Responsible Party):
Hussein Abdul-Latif, University of Alabama at Birmingham

Brief Summary:
KRN23 is a fully human immunoglobulin monoclonal antibody (mAb) that binds to and inhibits the activity of fibroblast growth factor 23 (FGF23), leading to an increase in serum phosphorus levels. There are multiple disorders that result in unusually high circulating levels of FGF23, which in turn result in renal phosphate wasting and reduced 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. KRN23 has been studied in one of these disorders, X-linked hypophosphatemia (XLH). In single- and repeat-dose clinical studies in subjects with XLH, subcutaneous (SC) administration of KRN23 consistently increased and sustained serum phosphorus levels and tubular reabsorption of phosphate (TRP) without a major impact on urine calcium levels or vitamin D metabolism. Positive results were also observed in a nonclinical pharmacology model of XLH. It is hypothesized that KRN23 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. The primary objective is to study the effect of KRN23 treatment on normalizing age-adjusted fasting serum phosphorous levels in a single pediatric patient with Epidermal Nevus Syndrome associated hypophosphatemic rickets.

Condition or disease Intervention/treatment Phase
Epidermal Nevus Syndrome Drug: Crysvita (burosumab-twza) Treatment Phase 4

Detailed Description:
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. 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. KRN23 has been studied in one of these disorders, X-linked hypophosphatemia (XLH). In single- and repeat-dose clinical studies in subjects with XLH, subcutaneous (SC) administration of KRN23 consistently increased and sustained serum phosphorus levels and tubular reabsorption of phosphate (TRP) without a major impact on urine calcium levels or vitamin D metabolism. Positive results were also observed in a nonclinical pharmacology model of XLH. It is hypothesized that KRN23 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open Label Trial to Assess the Safety and Efficacy of KRN23, an Investigational Antibody to FGF23, in a Single Pediatric Patient With Epidermal Nevus Syndrome (ENS) and Associated Hypophosphatemic Rickets
Actual Study Start Date : July 31, 2020
Estimated Primary Completion Date : July 31, 2021
Estimated Study Completion Date : January 31, 2022


Arm Intervention/treatment
Experimental: Crysvita (burosumab-twza) Treatment

The starting dose will be 0.3 mg/kg to be given every 2 weeks. If required dose may be titrated with increments of 0.1 mg/kg/dose every 4 weeks up to a maximum of dose of 2.0mg/kg (not to exceed 90mg per dose) until phosphorus level is WNL.

Patient will receive study drug via SC injection to the abdomen, upper arms, thighs, or buttocks; the injection site will be rotated with each injection. If the dose level exceeds 1.5 mL in volume, the dose should be administered at two injection sites.

Duration of treatment is 52 weeks. Subjects that complete treatment through week 52 may have the option to continue KRN23 treatment. If this is warranted based on preliminary efficacy, the current protocol will be amended to allow for an extension.

Drug: Crysvita (burosumab-twza) Treatment
KRN23 is a fully human IgG1monoclonal antibody that binds to and inhibits the activity of FGF23, leading to an increase in serum phosphorus levels. It is a potential therapeutic candidate for the treatment of XLH, Tumor-Induced Osteomalacia (TIO), and the rickets/osteomalacia resulting from Epidermal Nevus Syndrome (ENS). All of these conditions are diseases of bone hypomineralization, caused by urinary phosphate wasting due to elevated levels of FGF23.




Primary Outcome Measures :
  1. The participant will achieve normal age-adjusted phosphorous levels as tested by fasting serum lab values [ Time Frame: baseline levels prior to drug administration ]
    Normal phosphorous levels are between 3.5 and 5.9. Participant will have fasting levels drawn prior to drug administration

  2. The participant will achieve normal age-adjusted phosphorous levels as tested by fasting serum lab values [ Time Frame: baseline levels to 6 month drug levels ]
    Normal phosphorous levels are between 3.5 and 5.9. Participant will have fasting levels drawn every two weeks

  3. The participant will achieve normal age-adjusted phosphorous levels as tested by fasting serum lab values [ Time Frame: baseline levels to 12 month drug levels ]
    Normal phosphorous levels are between 3.5 and 5.9. Participant will have fasting levels drawn every two weeks


Secondary Outcome Measures :
  1. Participant will achieve improving Vitamin D levels as measured by serum blood tests. [ Time Frame: baseline levels prior to drug administration ]
    Normal Vitamin D levels are 5-42 ng/mL. Participant will have fasting levels drawn prior to drug administration

  2. Participant will achieve improving Vitamin D levels as measured by serum blood tests. [ Time Frame: baseline levels to levels after 6 months on drug ]
    Normal Vitamin D levels are 5-42 ng/mL. Participant will have fasting levels drawn every two weeks for the first 12 weeks of the study, then every 13 weeks until study completion.

  3. Participant will achieve improving Vitamin D levels as measured by serum blood tests. [ Time Frame: baseline levels to levels after 12 months on drug ]
    Normal Vitamin D levels are 5-42 ng/mL. Participant will have fasting levels drawn every two weeks for the first 12 weeks of the study, then every 13 weeks until study completion.

  4. Participant will achieve improving iPTH levels as measured by serum blood tests. [ Time Frame: baseline levels prior to drug administration ]
    Normal iPTH levels are 21.9 - 87.6 pg/mL.Participant will have fasting levels drawn prior to drug administration

  5. Participant will achieve improving iPTH levels as measured by serum blood tests. [ Time Frame: baseline levels to levels after 6 months on drug ]
    Normal iPTH levels are 21.9 - 87.6 pg/mL.Participant will have fasting levels drawn every two weeks for the first 12 weeks of the study, then every 13 weeks until study completion.

  6. Participant will achieve improving iPTH levels as measured by serum blood tests. [ Time Frame: baseline levels to levels after 12 months on drug ]
    Normal iPTH levels are 21.9 - 87.6 pg/mL. Participant will have fasting levels drawn every two weeks for the first 12 weeks of the study, then every 13 weeks until study completion.

  7. Participant will achieve improving calcium levels as measured by serum blood tests. [ Time Frame: baseline levels prior to drug administration ]
    Normal calcium levels are 9.2-10.5 mg/dL. Participant will have fasting levels drawn prior to drug administration

  8. Participant will achieve improving calcium levels as measured by serum blood tests. [ Time Frame: baseline levels to levels after 6 months on drug ]
    Normal calcium levels are 9.2-10.5 mg/dL. Participant will have fasting levels drawn every two weeks for the first 12 weeks of the study, then every 13 weeks until study completion.

  9. Participant will achieve improving calcium levels as measured by serum blood tests. [ Time Frame: baseline levels to levels after 12 months on drug ]
    Normal calcium levels are 9.2-10.5 mg/dL. Participant will have fasting levels drawn every two weeks for the first 12 weeks of the study, then every 13 weeks until study completion.

  10. Participant will achieve improving tubular reabsorption of phosphorous levels dependent on urine and serum phosphorous and creatinine levels. [ Time Frame: Baseline levels prior to drug administration ]
    Tubular reabsorption of phosphorous is based on a calculation of the ratio of urine phosphorous and serum creatinine to serum phosphorous and urine creatinine. It will measure the amount of phosphorous being absorbed by bone.

  11. Participant will achieve improving tubular reabsorption of phosphorous levels dependent on urine and serum phosphorous and creatinine levels. [ Time Frame: Baseline levels to levels after 12 months on drug ]
    Tubular reabsorption of phosphorous is based on a calculation of the ratio of urine phosphorous and serum creatinine to serum phosphorous and urine creatinine. It will measure the amount of phosphorous being absorbed by bone.

  12. Participant will achieve improving TmP/GFR rates as measured by a calculation of serum blood tests. [ Time Frame: baseline levels prior to drug administration ]
    TmP/GFR is based on a calculation of the ratio of tubular reabsorption of phosphorous levels to the glomerular filtration rate. This will measure how much phosphorous is being filtered by the kidneys.

  13. Participant will achieve improving TmP/GFR rates as measured by a calculation of serum blood tests. [ Time Frame: baseline levels to levels after 12 months on drug ]
    TmP/GFR is based on a calculation of the ratio of tubular reabsorption of phosphorous levels to the glomerular filtration rate. This will measure how much phosphorous is being filtered by the kidneys.

  14. Participant will achieve improvement of underlying skeletal disease/rickets as assessed by standard radiographs. [ Time Frame: baseline scans prior to drug administration ]
    DEXA scans and whole body x-rays will be taken at baseline prior to drug administration and at 12 months on drug. They will be assessed utilizing the Radiographic Global Impression of Change (RGI-C) rating scales.

  15. Participant will achieve improvement of underlying skeletal disease/rickets as assessed by standard radiographs. [ Time Frame: baseline scans prior to drug administration to scans after 12 months on drug ]
    DEXA scans and whole body x-rays will be taken at baseline prior to drug administration and at 12 months on drug. They will be assessed utilizing the Radiographic Global Impression of Change (RGI-C) rating scales.

  16. Participant will achieve improving levels of alkaline phosphatase (ALP), a biochemical marker of bone turnover as measured by serum blood tests [ Time Frame: baseline levels prior to drug administration ]
    Normal ALP levels are 127-517 U/L. Participant will have fasting levels drawn prior to drug administration

  17. Participant will achieve improving levels of alkaline phosphatase (ALP), a biochemical marker of bone turnover as measured by serum blood tests [ Time Frame: baseline levels to levels after 6 months on drug ]
    Normal ALP levels are 127-517 U/L. Participant will have fasting levels drawn every two weeks until study completion.

  18. Participant will achieve improving levels of alkaline phosphatase (ALP), a biochemical marker of bone turnover as measured by serum blood tests [ Time Frame: baseline levels to levels after 12 months on drug ]
    Normal ALP levels are 127-517 U/L. Participant will have fasting levels drawn every two weeks until study completion.

  19. Participant will achieve improving scores on self-reported outcome measures related to his disease process [ Time Frame: baseline self-assessment scores prior to drug administration ]
    The Patient-Reported Outcomes Measurement Information System (PROMIS) which includes pain interference, faces pain scale, and fatigue measurements will be administered to the patient at baseline prior to drug administration and every 6 months until study completion (currently study completion is slated for 12 months). This is a validated measurement tool. The possible scores are 0-104 with 0 being the best score. The mean score is 50 with a standard deviation of 10.

  20. Participant will achieve improving scores on self-reported outcome measures related to his disease process [ Time Frame: baseline self-assessment scores prior to drug administration to scores after 6 months on drug ]
    The Patient-Reported Outcomes Measurement Information System (PROMIS) which includes pain interference, faces pain scale, and fatigue measurements will be administered to the patient at baseline prior to drug administration and every 6 months until study completion (currently study completion is slated for 12 months). This is a validated measurement tool. The possible scores are 0-104 with 0 being the best score. The mean score is 50 with a standard deviation of 10.

  21. Participant will achieve improving scores on self-reported outcome measures related to his disease process [ Time Frame: baseline self-assessment scores prior to drug administration to scores after 12 months on drug ]
    The Patient-Reported Outcomes Measurement Information System (PROMIS) which includes pain interference, faces pain scale, and fatigue measurements will be administered to the patient at baseline prior to drug administration and every 6 months until study completion (currently study completion is slated for 12 months). This is a validated measurement tool. The possible scores are 0-104 with 0 being the best score. The mean score is 50 with a standard deviation of 10.



Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient has confirmed ENS by physician diagnosis
  • Patient has confirmed FGF23 elevations in the context of low serum phosphorous < 4.1 mg/dL
  • Patient able to tolerate KRN23 treatment
  • Have a corrected serum calcium level < 10.8mg/dL
  • Have an eGFR >60 ml/min
  • Must be willing in the opinion of the investigator, to comply with study procedures and schedule
  • Provide written informed consent by a parent after

Exclusion Criteria:

  • Patient should not use CRYSVITA with Oral phosphate or active Vitamin D analogs.
  • Patient and investigator should not initiate CRYSVITA if Phosphorus level is within or above normal.
  • CRYSVITA is contraindicated in patients with severe renal impairment or end stage renal disease because these conditions are associated with abnormal mineral metabolism.
  • The use or enrollment in studies using other investigational therapies including other monoclonal antibodies
  • Subject and their Parent not willing or not able to give written informed consent
  • In the Investigators opinion, the subject may not be able to meet all the requirements for study participation
  • Subject has a history of hypersensitivity to KRN23 excipients that in the opinion of the investigator, places the subject at an increased risk of adverse effects
  • Subject has a condition that in the opinion of the investigator could present a concern for subject safety or data interpretation.

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): NCT04320316


Locations
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United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35233
Sponsors and Collaborators
University of Alabama at Birmingham
Ultragenyx Pharmaceutical Inc
Investigators
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Principal Investigator: Hussein Abdul-Latif, MD University of Alabama at Birmingham
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Responsible Party: Hussein Abdul-Latif, Principal Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT04320316    
Other Study ID Numbers: IRB-300004900
First Posted: March 25, 2020    Key Record Dates
Last Update Posted: August 14, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: To be determined

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hussein Abdul-Latif, University of Alabama at Birmingham:
epidermal nevus syndrome
burosumab-twza
Additional relevant MeSH terms:
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Nevus
Nevus, Sebaceous of Jadassohn
Syndrome
Disease
Pathologic Processes
Nevi and Melanomas
Neoplasms by Histologic Type
Neoplasms
Neurocutaneous Syndromes
Nervous System Diseases
Abnormalities, Multiple
Congenital Abnormalities