Long-Term Extension Study of KRN23 in Adult Subjects With X-Linked Hypophosphatemia (XLH)

• ClinicalTrials.gov Identifier: NCT02312687
• Recruitment Status: Completed
• First Posted: December 9, 2014
• Results First Posted: December 16, 2019
• Last Update Posted: December 16, 2019
• Sponsor: Ultragenyx Pharmaceutical Inc
• Collaborator: Kyowa Kirin Co., Ltd.
• Information provided by (Responsible Party): Ultragenyx Pharmaceutical Inc

Tracking Information

• First Submitted Date: December 3, 2014
• First Posted Date: December 9, 2014
• Results First Submitted Date: November 26, 2019
• Results First Posted Date: December 16, 2019
• Last Update Posted Date: December 16, 2019
• Actual Study Start Date: January 30, 2015
• Actual Primary Completion Date: November 30, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 26, 2019)

• Number of Participants With Adverse Events (AEs), Treatment Emergent AEs (TEAEs), Serious AEs (SAEs), and AEs Leading to Discontinuation or Death [ Time Frame: Screening through the end of study plus 4-8 weeks. The mean duration of burosumab exposure was 165.6 weeks (range: 68-184 weeks). ]
  An AE is defined as any untoward medical occurrence, whether or not considered drug related. An SAE or serious suspected adverse reaction is an AE or suspected adverse reaction that at any dose, in the view of either the investigator or sponsor, results in any of the following outcomes: death; a life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect; an important medical event. A TEAE is an AE that occurred on or after the first burosumab dose. AEs were graded as 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening), 5 (death). AEs were classified by the Investigator as possibly related, probably related, or definitely related.
• Number of Participants With Clinically Significant Changes From Baseline in Vital Signs [ Time Frame: Through Week 184 ]
  Clinically significant changes from baseline reported as adverse events are presented.
• Number of Participants With Clinically Significant Changes From Baseline in Laboratory Values, by Category [ Time Frame: Through Week 184 ]
  Clinically significant changes from baseline reported as adverse events are presented.
• Number of Participants With Clinically Significant Changes From Baseline in Physical Exams, by Category [ Time Frame: Through Week 184 ]
  Clinically significant changes from baseline reported as adverse events are presented.
• Number of Participants With Clinically Significant Changes From Baseline in Echocardiogram (ECHO) Tests [ Time Frame: Through Week 184 ]
  Clinically significant changes from baseline reported as adverse events are presented.
• Number of Participants With Clinically Significant Changes From Baseline in ECGs [ Time Frame: Through Week 184 ]
  Clinically significant changes from baseline reported as adverse events are presented.
• Number of Participants With Clinically Significant Changes From Baseline in Renal Ultrasound, by Category [ Time Frame: Through Week 184 ]
  Clinically significant changes from baseline reported as adverse events are presented.
• Number of Participants Positive for Anti-KRN23 Antibodies and Neutralizing Antibodies at Baseline and Anytime Post-Baseline [ Time Frame: Through Week 184 ]
• Percentage of Participants Reaching Serum Phosphorus Normal Range at Baseline and Any Time After Dosing [ Time Frame: Through Week 184 ]
• Change From Baseline Over Time in Serum Phosphorus [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]
• Change From Baseline Over Time in Serum iPTH [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]
• Change From Baseline Over Time in Serum Total FGF23 [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]
• Change From Baseline Over Time in Serum Free FGF23 [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]
• Change From Baseline Over Time in Serum 1,25(OH)2D [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]
• Change From Baseline Ovr Time in 2-hour Urine TmP/GFR [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]
• Change From Baseline Over Time in in 2-hour Urine TRP [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]
• Change From Baseline Over Time in FEP [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]
• Change From Baseline Over Time in 24-hour Urine Phosphorus [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]
• Change From Baseline Over Time in 24-Hour Urine Calcium [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]
• Change From Baseline Over Time in 24-Hour Urine Creatinine [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]
• Change From Baseline Over Time in 24-Hour Urine Calcium/Creatinine Ratio [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]
• Change From Baseline Over Time in Total ALP [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]
• Change From Baseline Over Time in BALP [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]
• Change From Baseline Over Time in CTx [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]
• Change From Baseline Over Time in P1NP [ Time Frame: Baseline, Weeks 24, 48, 72, 96, 120, 144 ]

• Original Primary Outcome Measures (submitted: December 5, 2014): Incidence, frequency, and severity of adverse events and serious adverse events [ Time Frame: 72 Weeks ]
• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (submitted: December 5, 2014)

• Change from Baseline in serum FGF23 [ Time Frame: 72 Weeks ]
• Change from Baseline in serum ALP [ Time Frame: 72 Weeks ]
• Change from Baseline in serum 1,25(OH)2D [ Time Frame: 72 Weeks ]
• Change from Baseline in serum iPTH [ Time Frame: 72 Weeks ]
• Change from Baseline in serum and urine phosphorus [ Time Frame: 72 Weeks ]
• Change from Baseline in serum TRP and TMP/GFR [ Time Frame: 72 Weeks ]
• Change from Baseline in serum BALP [ Time Frame: 72 Weeks ]
• Change from Baseline in serum CTx [ Time Frame: 72 Weeks ]
• Change from Baseline in serum P1NP [ Time Frame: 72 Weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: December 5, 2014)

• Evaluate bone health through standard radiographs of legs, feet, and lateral spine and areas of pain/fractures [ Time Frame: 72 Weeks ]
• Brief Pain Inventory (BPI) [ Time Frame: 72 Weeks ]
• Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) [ Time Frame: 72 Weeks ]
• Short Form Health Survey (SF-36) [ Time Frame: 72 Weeks ]
• 6 Minute Walk Test (6MWT) [ Time Frame: 72 Weeks ]
• Timed up and go (TUG) [ Time Frame: 72 Weeks ]
• 3 Minute Stair Climb Test (3MSCT) [ Time Frame: 72 Weeks ]

Descriptive Information

• Brief Title: Long-Term Extension Study of KRN23 in Adult Subjects With X-Linked Hypophosphatemia (XLH)
• Official Title: A Phase 2b, Open-Label, Long-Term Extension Study to Evaluate the Safety and Pharmacodynamics of KRN23 in Adult Subjects With X-Linked Hypophosphatemia (XLH)

Brief Summary

The primary objectives of this study are to:

• Assess the long-term safety of KRN23 subcutaneous (SC) administration in adult subjects with XLH
• Assess the proportion of subjects achieving serum phosphorus levels in the normal range (2.5-4.5 mg/dL) with long-term administration of KRN23
• Assess long-term pharmacodynamics (PD) of KRN23 as measured by changes in the following: serum intact parathyroid hormone (iPTH); serum and urinary phosphorus; ratio of renal tubular maximum phosphate reabsorption rate to glomerular filtration rate (TmP/GFR) and tubular reabsorption of phosphate (TRP); serum 1,25-dihydroxy vitamin D (1,25[OH]2D); serum fibroblast growth factor 23 (FGF23); bone biomarkers: serum alkaline phosphatase (ALP), bone-specific ALP (BALP), carboxy terminal crosslinked telopeptide of type I collagen (CTx), and procollagen type 1 N-terminal propeptide (P1NP)
• Assess long-term immunogenicity of KRN23 as measured by presence of anti-KRN23 antibody (ADA)

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: X-Linked Hypophosphatemia

Intervention

Biological: KRN23

solution for SC injection

Other Names:

• burosumab
• Crysvita®

Study Arms

Experimental: KRN23

KRN23 subcutaneous (SC) injections every 4 weeks. Starting doses will be based on the subject's last dose in study KRN23-INT-001 (NCT02312687) or KRN23-INT-002 (NCT01571596). Doses may be titrated to achieve the target peak serum phosphorus range.

Intervention: Biological: KRN23

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 31, 2018): 20
• Original Estimated Enrollment (submitted: December 5, 2014): 25
• Actual Study Completion Date: November 30, 2018
• Actual Primary Completion Date: November 30, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Have participated in Kyowa Hakko Kirin Pharma, Inc.'s KRN23-INT-001 (NCT01340482) or KRN23-INT-002 (NCT01571596) studies (received at least 2 doses of KRN23)
2. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min or eGFR of 45 to < 60 mL/min at Screening with confirmation that the renal insufficiency was not due to nephrocalcinosis.
3. Sexually active subjects must be willing to use an acceptable method of contraception (e.g., double barrier method) while participating in the study and for 30 days after receiving the last dose of KRN23.

Exclusion Criteria:

1. Subject experienced a safety-related event in the KRN23-INT-001 or KRN23-INT-002 study that, in the opinion of the investigator and sponsor, precludes resuming KRN23 treatment.
2. Presence of nephrocalcinosis on renal ultrasound that, in the opinion of the investigator and sponsor, precludes resuming KRN23 treatment.
3. Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at any time during the study.
4. Participation in an investigational drug or device trial within 30 days of enrollment (other than KRN23-INT-001 or KRN23-INT-002).
5. Use of a pharmacologic vitamin D metabolite or analog (e.g., calcitriol, doxercalciferol, and paricalcitol), phosphate, or aluminum hydroxide antacids (e.g., Maalox® and Mylanta®) within 21 days prior to Screening or during the study.
6. Use of medication to suppress parathyroid hormone (PTH) (e.g., Sensipar®, cinacalcet, calcimimetics) within 2 months prior to Screening.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02312687
• Other Study ID Numbers: UX023-CL203
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Ultragenyx Pharmaceutical Inc
• Study Sponsor: Ultragenyx Pharmaceutical Inc
• Collaborators: Kyowa Kirin Co., Ltd.

Investigators

• Study Director: Medical Director; Ultragenyx Pharmaceutical Inc

• PRS Account: Ultragenyx Pharmaceutical Inc
• Verification Date: November 2019