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

Study Overview
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Brief Summary
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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).

Official Title
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An Open-Label, Single-Arm, Phase 3 Study to Evaluate the Effects of KRN23 on Osteomalacia in Adults With X-linked Hypophosphatemia (XLH)

Conditions
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X-linked Hypophosphatemia

Intervention / Treatment
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* Biological: burosumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged 18 - 65 years, inclusive 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 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 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) 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 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 Willing to provide access to prior medical records for the collection of biochemical and radiographic data and disease history 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. 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 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: Use of any pharmacologic vitamin D metabolite or analog (e.g. calcitriol, doxercalciferol, and paricalcitol) within the 2 years before Screening Use of oral phosphate within 2 years before Screening Use of aluminum hydroxide antacids, acetazolamides, and thiazides within 7 days prior to Screening Use of bisphosphonates in the 2 years prior to Screening Use of denosumab in the 6 months prior to Screening Use of teriparatide in the 2 months prior to Screening Chronic use of systemic corticosteroids defined as more than 10 days in the 2 months prior to Screening Corrected serum calcium level ≥ 10.8 mg/dL (2.7 mmol/L) at Screening Serum intact parathyroid hormone (iPTH) ≥ 2.5 times the upper limit of normal (ULN) at Screening Use of medication to suppress parathyroid hormone (PTH) (cinacalcet for example) within 60 days prior to Screening Prothrombin time/Partial thromboplastin time (PT/PTT) outside the normal range at Screening 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 Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at any time during the study Unable or unwilling to withhold prohibited medications throughout the study Documented dependence on narcotics Use of KRN23, or any other therapeutic monoclonal antibody within 90 days prior to Screening 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. 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 History of allergic reaction or adverse reactions to tetracycline or demeclocycline Prior history of positive test for human immunodeficiency virus antibody, hepatitis B surface antigen, and/or hepatitis C antibody History of recurrent infection (other than dental abscesses, which are known to be associated with XLH) or predisposition to infection, or of known immunodeficiency Presence of malignant neoplasm (except basal cell carcinoma) Presence of a concurrent disease or condition that would interfere with study participation or affect safety 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-Label Burosumab Q4W<br>1.0 mg/kg burosumab monthly (Q4W), calculated based on baseline weight and up to a maximum dose of 90 mg. | Biological: burosumab<br>* solution for subcutaneous injection<br>* Other names: Crysvita;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in OV/BV at Week 48 | OV/BV: percent of a given volume of bone tissue that consists of unmineralized bone (osteoid). | Baseline, 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | The LLN was defined as 2.5 mg/dL (0.81 mmol/L). The 95% confidence interval (CI) was calculated using Wilson score method. | Baseline, up to 24 weeks | 
| Percent Change From Baseline in O.Th at Week 48 | O.Th: mean thickness, given in micrometers, for osteoid seams. | Baseline, 48 weeks | 
| Percent Change From Baseline in OS/BS at Week 48 | OS/Bs: percent of bone surface covered in osteoid. | Baseline, 48 weeks | 
| Percent Change From Baseline in MLt at Week 48 | 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. | Baseline, 48 weeks | 
| Change From Baseline in MAR at Week 48 | MAR: linear rate of new bone deposition; mean distance between the double labels, divided by the time interval between them. | Baseline, 48 weeks | 
| Change From Baseline in MS/BS at Week 48 | 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. | Baseline, 48 weeks | 
| Change From Baseline in BFR/BS at Week 48 | 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. | Baseline, 48 weeks | 
| Change From Baseline in BFR/OS at Week 48 | 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]). | Baseline, 48 weeks | 
| Change From Baseline in BFR/BV at Week 48 | BFR/BV: equivalent to bone turnover rate. | Baseline, 48 weeks | 
| Percentage of Participants Achieving Mean Serum Phosphorus Levels Above the LLN at the End of the Dosing Cycle Between Baseline and Week 24 | The LLN was defined as 2.5 mg/dL (0.81 mmol/L). The 95% CI was calculated using Wilson score method. | Baseline, up to 24 weeks | 
| Mean Change of Serum Phosphorus Levels at the Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 |  | Baseline, up to 24 weeks | 
| Percent Change of Serum Phosphorus Levels at the Mid-Point of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 |  | Baseline, up to 24 weeks | 
| Mean Change of Serum Phosphorus Levels at the End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 |  | Baseline, up to 24 weeks | 
| Percentage Change of Serum Phosphorus Levels at the End of Dosing Cycle, as Averaged Across Dose Cycles Between Baseline and Week 24 |  | Baseline, up to 24 weeks | 
| Time-Adjusted Area Under the Curve (AUC) of Serum Phosphorus Between Baseline and Week 24 |  | Baseline, up to 24 weeks | 
| Change From Baseline Over Time in Serum 1,25(OH)2D |  | Baseline, Week 1, Week 2, Week 4, Week 20, Week 21, Week 22, Week 24, Week 48, Week 60, Week 70, Week 72, Week 84, Week 94, Week 96, Week 108, Week 120, Week 132 | 
| Change From Baseline Over Time in 24-Hour Urinary Phosphorus |  | Baseline, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96, End of Study II (EOSII) (up to Week 141) | 
| Change From Baseline Over Time in TmP/GFR | TmP/GFR: ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate. | Baseline, Week 2, Week 4, Week 12, Week 22, Week 24, Week 48, Week 60, Week 72, Week 84, Week 96, EOSII (up to Week 141) | 
| Change From Baseline Over Time in TRP | TRP: tubular reabsorption of phosphate. | Baseline, Week 2, Week 4, Week 12, Week 22, Week 24, Week 48, Week 60, Week 72, Week 84, Week 96, EOSII (up to Week 141) | 
| Change From Baseline Over Time in P1NP | P1NP: procollagen type 1 N-propeptide. | Baseline, Week 12, Week 24, Week 48, Week 72, Week 96, EOSII (up to Week 141) | 
| Percent Change From Baseline Over Time in P1NP |  | Baseline, Week 12, Week 24, Week 48, Week 72, Week 96, EOSII (up to Week 141) | 
| Change From Baseline Over Time in CTx | CTx: carboxy-terminal cross-linked telopeptide of type I collagen. | Baseline, Week 12, Week 24, Week 48, Week 72, Week 96, EOSII (up to Week 141) | 
| Percent Change From Baseline Over Time in CTx | CTx: carboxy-terminal cross-linked telopeptide of type I collagen. | Baseline, Week 12, Week 24, Week 48, Week 72, Week 96, EOSII (up to Week 141) | 
| Change From Baseline Over Time in BALP | BALP: bone-specific alkaline phosphatase. | Baseline, Week 12, Week 24, Week 48, Week 72, Week 96, EOSII (up to Week 141) | 
| Percent Change From Baseline Over Time in BALP | BALP: bone-specific alkaline phosphatase. | Baseline, Week 12, Week 24, Week 48, Week 72, Week 96, EOSII (up to Week 141) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KRN23, Fibroblast growth factor 23 (FGF23), XLH, X-linked Hypophosphatemia