Overview

This trial is active, not recruiting.

Condition x-linked hypophosphatemia
Treatment krn23
Phase phase 3
Sponsor Ultragenyx Pharmaceutical Inc
Collaborator Kyowa Hakko Kirin Company, Limited
Start date December 2015
End date August 2017
Trial size 14 participants
Trial identifier NCT02537431, UX023-CL304

Summary

UX023-CL304 is a Phase 3 open-label, single-arm, multicenter study to establish the effects of KRN23 on bone quality and osteomalacia associated with XLH. Approximately 14 adult subjects with a diagnosis of XLH supported by typical clinical and biochemical features and who have not received oral phosphate and vitamin D therapy in the past two years will be enrolled. Iliac crest bone biopsies will be performed at baseline and end of study. Baseline histologic and histomorphometric assessments of the bone biopsy specimens will be performed as each biopsy is completed to assess sample quality and confirm the presence of osteomalacia in at least 8 subjects.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
All subjects will receive 1.0 mg/kg KRN23 monthly (Q4W, 28 days) rounded to the nearest 10 mg. The amount of drug administered will be calculated based on baseline weight and a 1.0 mg/kg KRN23 dose level (rounded to the nearest 10 mg) up to a maximum dose of 90 mg.
krn23
KRN23 is a recombinant human immunoglobulin G isotype 1 (IgG1) monoclonal antibody (mAb) that binds to and inhibits the activity of fibroblast growth factor 23 (FGF23).

Primary Outcomes

Measure
Osteoid Thickness (O.Th)
time frame: 48 weeks
Osteoid surface/Bone surface (OS/BS)
time frame: 48 weeks
Mineralization lag time (MLt)
time frame: 48 weeks
Osteoid volume/Bone volume (OV/BV)
time frame: 48 weeks

Secondary Outcomes

Measure
Proportion of subjects achieving mean serum phosphorus levels above the lower limit of normal (LLN) at the mid-point of the dose interval (i.e., Weeks 2, 6, 14, and 22), as averaged across dose cycles between baseline and Week 24.
time frame: 24 weeks
Changes in mineral apposition rate (MAR)
time frame: 48 weeks
Changes in mineralizing surface (MS/BS)
time frame: 48 weeks
Changes in bone formation rate (BFR)
time frame: 48 weeks
Proportion of subjects achieving mean serum phosphorus levels above the Lower Limit of Normal (LLN) at the end of the dosing cycle
time frame: 24 weeks
Mean change of serum phosphorus levels at the mid-point of dosing cycle and end of dosing cycle
time frame: 24 weeks
Percentage change of serum phosphorus levels at the mid-point of dosing cycle and end of dosing cycle
time frame: 24 weeks
Cumulative exposure of serum phosphorus levels: area under the curve (AUC)
time frame: 24 weeks
Change from baseline over time in serum 1,25(OH)2D
time frame: 24 weeks
Change from baseline over time in urinary phosphorus
time frame: 24 weeks
Change from baseline over time in ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR)
time frame: 24 weeks
Change from baseline over time in tubular reabsorption of phosphate (TRP)
time frame: 24 weeks
Change from baseline over time in procollagen type 1 N-propeptide (P1NP)
time frame: 24 weeks
Change from baseline over time in carboxy-terminal cross-linked telopeptide of type I collagen (CTx)
time frame: 24 weeks
Change from baseline over time in bone-specific alkaline phosphatase (BALP)
time frame: 24 weeks
Percent change from baseline over time in procollagen type 1 N-propeptide (P1NP), carboxy-terminal cross-linked telopeptide of type I collagen (CTx), and bone-specific alkaline phosphatase (BALP)
time frame: 24 weeks

Eligibility Criteria

Male or female participants from 18 years up to 65 years old.

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 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 - 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 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 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

Additional Information

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)
Trial information was received from ClinicalTrials.gov and was last updated in September 2016.
Information provided to ClinicalTrials.gov by Ultragenyx Pharmaceutical Inc.