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Open Label Study of KRN23 on Osteomalacia in Adults With X-linked Hypophosphatemia (XLH)

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ClinicalTrials.gov Identifier: NCT02537431
Recruitment Status : Active, not recruiting
First Posted : September 1, 2015
Results First Posted : September 25, 2018
Last Update Posted : November 14, 2018
Sponsor:
Collaborator:
Kyowa Hakko Kirin Co., Ltd
Information provided by (Responsible Party):
Ultragenyx Pharmaceutical Inc

Brief Summary:
The primary objective of this study is to establish the effect of KRN23 treatment on improvement in XLH-associated osteomalacia as determined by osteoid volume (osteoid volume/bone volume, OV/BV).

Condition or disease Intervention/treatment Phase
X-linked Hypophosphatemia Biological: burosumab Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Single-Arm, Phase 3 Study to Evaluate the Effects of KRN23 on Osteomalacia in Adults With X-linked Hypophosphatemia (XLH)
Actual Study Start Date : December 23, 2015
Actual Primary Completion Date : August 30, 2017
Estimated Study Completion Date : November 30, 2018


Arm Intervention/treatment
Experimental: Open-Label Burosumab Q4W
1.0 mg/kg burosumab monthly (Q4W), calculated based on baseline weight and up to a maximum dose of 90 mg.
Biological: burosumab
solution for subcutaneous injection
Other Names:
  • KRN23
  • UX023
  • Crysvita




Primary Outcome Measures :
  1. Percent Change From Baseline in OV/BV at Week 48 [ Time Frame: Baseline, 48 weeks ]
    OV/BV: percent of a given volume of bone tissue that consists of unmineralized bone (osteoid).


Secondary Outcome Measures :
  1. Percentage of Participants Achieving Mean Serum Phosphorus Levels Above the Lower Limit of Normal (LLN) at the Mid-Point of the Dose Interval, as Averaged Across Dose Cycles Between Baseline and Week 24 [ Time Frame: Baseline, up to 24 weeks ]
    The LLN was defined as 2.5 mg/dL (0.81 mmol/L). The 95% confidence interval (CI) was calculated using Wilson score method.

  2. Percent Change From Baseline in O.Th at Week 48 [ Time Frame: Baseline, 48 weeks ]
    O.Th: mean thickness, given in micrometers, for osteoid seams.

  3. Percent Change From Baseline in OS/BS at Week 48 [ Time Frame: Baseline, 48 weeks ]
    OS/Bs: percent of bone surface covered in osteoid.

  4. Percent Change From Baseline in MLt at Week 48 [ Time Frame: Baseline, 48 weeks ]
    MLt: average time interval between osteoid formation and its subsequent mineralization; calculated by dividing the osteoid thickness by the adjusted apposition rate (O.Th/Aj.AR). Aj.AR; amount of new bone created (bone formation rate over the entire osteoid surface). Based on imputed MLt values.

  5. Change From Baseline in MAR at Week 48 [ Time Frame: Baseline, 48 weeks ]
    MAR: linear rate of new bone deposition; mean distance between the double labels, divided by the time interval between them.

  6. Change From Baseline in MS/BS at Week 48 [ Time Frame: Baseline, 48 weeks ]
    MS/BS: percent of bone surface that displays a tetracycline label reflecting active mineralization; calculated as the double-labeled surface plus one half of the single-labeled surface and is expressed as a function of total bone surface ([dLS + sLS/2]/BS). It is a measure of the proportion of bone surface upon which new mineralized bone was being deposited during the period of tetracycline labeling.

  7. Change From Baseline in BFR/BS at Week 48 [ Time Frame: Baseline, 48 weeks ]

    BFR/BS: amount of new bone formed in unit time per unit of bone surface; calculated by multiplying MS/BS by the MAR.

    MS/BS: percent of bone surface that displays a tetracycline label reflecting active mineralization; calculated as the double-labeled surface plus one half of the single-labeled surface and is expressed as a function of total bone surface ([dLS + sLS/2]/BS). It is a measure of the proportion of bone surface upon which new mineralized bone was being deposited during the period of tetracycline labeling. MAR: linear rate of new bone deposition; mean distance between the double labels, divided by the time interval between them.


  8. Change From Baseline in BFR/OS at Week 48 [ Time Frame: Baseline, 48 weeks ]
    BFR/OS: bone formation rate to osteoid surface ratio, related to the Aj.AR (amount of new bone created [bone formation rate over the entire osteoid surface]).

  9. Change From Baseline in BFR/BV at Week 48 [ Time Frame: Baseline, 48 weeks ]
    BFR/BV: equivalent to bone turnover rate.

  10. Percentage of Participants Achieving Mean Serum Phosphorus Levels Above the LLN at the End of the Dosing Cycle Between Baseline and Week 24 [ Time Frame: Baseline, up to 24 weeks ]
    The LLN was defined as 2.5 mg/dL (0.81 mmol/L). The 95% CI was calculated using Wilson score method.

  11. Mean Change of Serum Phosphorus Levels at the Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 [ Time Frame: Baseline, up to 24 weeks ]
  12. Percent Change of Serum Phosphorus Levels at the Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 [ Time Frame: Baseline, up to 24 weeks ]
  13. Mean Change of Serum Phosphorus Levels at the End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 [ Time Frame: Baseline, up to 24 weeks ]
  14. Percentage Change of Serum Phosphorus Levels at the End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 [ Time Frame: Baseline, up to 24 weeks ]
  15. Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Between Baseline and Week 24 [ Time Frame: Baseline, up to 24 weeks ]
  16. Change From Baseline Over Time in Serum 1,25(OH)2D [ Time Frame: Baseline, Week 1, Week 2, Week 4, Week 20, Week 21, Week 22, Week 24, Week 48 ]
  17. Change From Baseline Over Time in 24-Hour Urinary Phosphorus [ Time Frame: Baseline, Week 12, Week 24, Week 36, Week 48 ]
  18. Change From Baseline Over Time in TmP/GFR [ Time Frame: Baseline, Week 2, Week 4, Week 12, Week 22, Week 24, Week 48 ]
    TmP/GFR: ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate.

  19. Change From Baseline Over Time in TRP [ Time Frame: Baseline, Week 2, Week 4, Week 12, Week 22, Week 24, Week 48 ]
    TRP: tubular reabsorption of phosphate.

  20. Change From Baseline Over Time in P1NP [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    P1NP: procollagen type 1 N-propeptide.

  21. Percent Change From Baseline Over Time in P1NP [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    P1NP: procollagen type 1 N-propeptide.

  22. Change From Baseline Over Time in CTx [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    CTx: carboxy-terminal cross-linked telopeptide of type I collagen.

  23. Percent Change From Baseline Over Time in CTx [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    CTx: carboxy-terminal cross-linked telopeptide of type I collagen.

  24. Change From Baseline Over Time in BALP [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    BALP: bone-specific alkaline phosphatase.

  25. Percent Change From Baseline Over Time in BALP [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    BALP: bone-specific alkaline phosphatase.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female, aged 18 - 65 years, inclusive
  2. Diagnosis of XLH supported by classic clinical features of adult XLH (such as short stature or bowed legs), and at least one of the following at Screening:

    • Documented phosphate regulating gene with homology to endopeptidases located on the X chromosome (PHEX) PHEX mutation in either the patient or in a directly related family member with appropriate X-linked inheritance
    • Serum intact FGF23 (iFGF23) level > 30 pg/mL by Kainos assay
  3. Biochemical findings consistent with XLH based on overnight fasting (min. 8 hours):

    • Serum phosphorus < 2.5 mg/dL at Screening
    • Ratio of renal tubular maximum phosphate reabsorption rate to glomerular filtration rate (TmP/GFR) < 2.5 mg/dL at Screening
  4. Presence of skeletal pain attributed to XLH/osteomalacia, as defined by a score of ≥ 4 on the Brief Pain Inventory question 3 (BPI-Q3, Worst Pain) at Screening. (Skeletal pain that, in the opinion of the investigator, is attributed solely to causes other than XLH/osteomalacia—for example, back pain or joint pain in the presence of severe osteoarthritis by radiograph in that anatomical location—in the absence of any skeletal pain likely attributed to XLH/osteomalacia should not be considered for eligibility)
  5. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) or estimated glomerular filtration rate (eGFR) eGFR of 45 to <60 mL/min at Screening with confirmation that the renal insufficiency is not due to nephrocalcinosis
  6. Provide written informed consent after the nature of the study has been explained, and prior to any research-related procedures. If the subject in a minor, provide written assent and have a legally authorized representative willing and able to provide written informed consent, after the nature of the study has been explained, and prior to any research-related procedures
  7. Willing to provide access to prior medical records for the collection of biochemical and radiographic data and disease history
  8. Females of child-bearing potential must have a negative urine pregnancy test at Screening and be willing to have additional pregnancy tests during the study. Females considered not to be of childbearing potential include those who have been in menopause for at least two years prior to Screening, or have had tubal ligation at least one year prior to Screening, or have had a total hysterectomy or bilateral salpingo-oophorectomy.
  9. Participants of child‐bearing potential or with partners of child-bearing potential who have not undergone a total hysterectomy or a bilateral salpingo‐oophorectomy and are sexually active must consent to use two effective methods of contraception as determined by the site investigator (i.e. oral hormonal contraceptives, patch hormonal contraceptives, vaginal ring, intrauterine device, physical double-barrier methods, surgical hysterectomy, vasectomy, tubal ligation, or true abstinence) from the period following the signing of the informed consent through 12 weeks after last dose of study drug
  10. 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

Exclusion Criteria:

  1. Use of any pharmacologic vitamin D metabolite or analog (e.g. calcitriol, doxercalciferol, and paricalcitol) within the 2 years before Screening
  2. Use of oral phosphate within 2 years before Screening
  3. Use of aluminum hydroxide antacids, acetazolamides, and thiazides within 7 days prior to Screening
  4. Use of bisphosphonates in the 2 years prior to Screening
  5. Use of denosumab in the 6 months prior to Screening
  6. Use of teriparatide in the 2 months prior to Screening
  7. Chronic use of systemic corticosteroids defined as more than 10 days in the 2 months prior to Screening
  8. Corrected serum calcium level ≥ 10.8 mg/dL (2.7 mmol/L) at Screening
  9. Serum intact parathyroid hormone (iPTH) ≥ 2.5 times the upper limit of normal (ULN) at Screening
  10. Use of medication to suppress parathyroid hormone (PTH) (cinacalcet for example) within 60 days prior to Screening
  11. Prothrombin time/Partial thromboplastin time (PT/PTT) outside the normal range at Screening
  12. Evidence of any disease or use of anticoagulant medication (such as warfarin, heparin, direct thrombin inhibitors, or Xa inhibitors (xabans) that, in the opinion of the investigator, cannot be discontinued) that may increase the risk of bleeding during the biopsy procedure
  13. Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at any time during the study
  14. Unable or unwilling to withhold prohibited medications throughout the study
  15. Documented dependence on narcotics
  16. Use of KRN23, or any other therapeutic monoclonal antibody within 90 days prior to Screening
  17. Use of 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.

    OR, in Japan, use of any investigational product or investigational medical device within 4 months prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.

  18. Presence or history of any hypersensitivity, allergic or anaphylactic reactions to any monoclonal antibody or KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects
  19. History of allergic reaction or adverse reactions to tetracycline or demeclocycline
  20. Prior history of positive test for human immunodeficiency virus antibody, hepatitis B surface antigen, and/or hepatitis C antibody
  21. History of recurrent infection (other than dental abscesses, which are known to be associated with XLH) or predisposition to infection, or of known immunodeficiency
  22. Presence of malignant neoplasm (except basal cell carcinoma)
  23. Presence of a concurrent disease or condition that would interfere with study participation or affect safety
  24. Presence or history of any condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or of not completing the study

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): NCT02537431


Locations
United States, California
UCSF Medical Center at Mission
San Francisco, California, United States, 94158
United States, Connecticut
Yale University School of Medicine - Yale New-Haven Hospital/Yale Center for Clinical Investigation
New Haven, Connecticut, United States, 06510
United States, Indiana
Indiana University Department of Medicine University Hospital
Indianapolis, Indiana, United States, 46202
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Texas
Houston Methodist Hospital
Houston, Texas, United States, 77030
Canada, Ontario
Children's Hospital of Eastern Ontario
Ottawa, Ontario, Canada, K1H 8L1
Canada, Quebec
Shriners Hospital for Children
Montreal, Quebec, Canada, H3G 1A6
Denmark
Aarhus University Hospital-Dept of Endocrinology and Internal Medicine
Aarhus, Denmark, 8000
France
CHU de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction
Le Kremlin-Bicêtre, France, 94275
CHU Paris Centre - Hôpital Cochin
Paris, France, 75014
Japan
Osaka University Hospital
Osaka, Japan, 565-0871
Hokkaido University Hospital
Sapporo, Japan, 060-8648
The University of Tokyo Hospital
Tokyo, Japan, 113-8655
Korea, Republic of
Seoul National University Hospital
Seoul, Korea, Republic of, 110-744
Sponsors and Collaborators
Ultragenyx Pharmaceutical Inc
Kyowa Hakko Kirin Co., Ltd
  Study Documents (Full-Text)

Documents provided by Ultragenyx Pharmaceutical Inc:
Study Protocol  [PDF] August 29, 2017
Statistical Analysis Plan  [PDF] December 15, 2016


Responsible Party: Ultragenyx Pharmaceutical Inc
ClinicalTrials.gov Identifier: NCT02537431     History of Changes
Other Study ID Numbers: UX023-CL304
First Posted: September 1, 2015    Key Record Dates
Results First Posted: September 25, 2018
Last Update Posted: November 14, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by Ultragenyx Pharmaceutical Inc:
KRN23
Fibroblast growth factor 23 (FGF23)
XLH
X-linked Hypophosphatemia

Additional relevant MeSH terms:
Hypophosphatemia
Osteomalacia
Familial Hypophosphatemic Rickets
Phosphorus Metabolism Disorders
Metabolic Diseases
Rickets
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Calcium Metabolism Disorders
Vitamin D Deficiency
Avitaminosis
Deficiency Diseases
Malnutrition
Nutrition Disorders
Rickets, Hypophosphatemic
Hypophosphatemia, Familial
Renal Tubular Transport, Inborn Errors
Kidney Diseases
Urologic Diseases
Metal Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn