The objectives of the study are to:* Identify a dose and dosing regimen of KRN23, based on safety and PD effect, in pediatric XLH patients* Establish the safety profile of KRN23 for the treatment of children with XLH including ectopic mineralization…
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacodynamic*:
* Serum phosphorus
* Serum 1,25(OH)2D
* Urinary phosphorus
* Phosphate reabsorption: ratio of renal tubular maximum reabsorption rate of
phosphate to glomerular filtration rate (TmP/GFR), and tubular reabsorption of
phosphate (TRP)
* Bone biomarkers: procollagen type 1 N-propeptide (P1NP), carboxy-terminal
cross-linked telopeptide of type I collagen (CTx), and alkaline phosphatase
(ALP)
* Blood and urine to be collected after a minimum overnight fasting time of 8
hours and prior to drug administration (if applicable) per dosing regimen
Efficacy * Bone Health:
* Growth: standing height, sitting height, arm length and leg length will be
measured. Growth percentiles based on standing height will be derived prior to
and following treatment if historical data are available
* Severity of rickets and epiphyseal (growth plate) abnormalities: central
readings of bilateral posteroanterior (PA) hand/wrist and anteroposterior (AP)
knee radiographs using a disease-specific qualitative Radiograph Global
Impression of Change (RGI-C) scoring system and a modified version of a scale
developed for nutritional rickets
* Lower extremity deformity assessed by intercondylar distance and
intermalleolar distance. Specific abnormalities related to lower extremity
deformity and bowing observed on standing long leg films will also be evaluated
using the qualitative RGI-C scoring system
* Bone Mineral Density or Content at the cortical and trabecular compartment as
assessed by XtremeCT of the forearm and tibia (performed at select sites
depending on availability of equipment)
Efficacy * Clinical Outcomes:
* Walking ability: Six Minute Walk Test (6MWT) total distance and percent of
predicted normal distance walked
* Gross motor function: Bruininks-Oseretsky Test of Motor Proficiency * Second
Edition (BOT-2) subtests to assess running speed, agility and strength
* Muscle strength: bilateral hand-held dynamometry (HHD) in the following
muscle groups: gross grip, knee flexors, knee extensors, hip flexors, hip
extensors and hip abductors
* Functional disability and pain: Pediatric Orthopedic Society of North America
Pediatric Outcomes Data Collection Instrument (POSNA PODCI)
* Health-Related Quality of Life: SF-10 for Children Health Survey (SF-10)
Pharmacokinetic:
* Serum KRN23 (pre-dose level)
Secondary outcome
Safety Assessments:
Safety will be evaluated by the incidence, frequency and severity of adverse
events (AEs) and serious adverse events (SAEs), including clinically
significant changes from baseline to scheduled time points.
General Safety Variables include:
* Vital signs and weight
* Interval history and physical examinations
* GFR
* Chemistry, hematology ,and urinalysis, including additional KRN23/XLH
biochemical parameters of interest (serum 25(OH)D, amylase, creatinine, and
iFGF23 [total, bound and unbound])
* Anti-KRN23 antibody testing and dose-limiting toxicities
* Concomitant medications
* ECG
Ectopic Mineralization Safety Assessments include:
* Renal ultrasound
* ECHO
* Serum calcium, phosphorus and iPTH; urinary calcium and creatinine
Background summary
X-linked hypophosphatemia (XLH) is a disorder of renal phosphate wasting, and
the most common heritable form of rickets. In XLH patients, high circulating
levels of fibroblast growth factor 23 (FGF23) impair normal phosphate
reabsorption in the kidney. Hypophosphatemia and low-normal circulating
1,25-dihydroxyvitamin D (1,25(OH)2D) levels are typical biochemical findings.
Low serum phosphorus levels result in hypomineralization of bone and associated
abnormalities including rickets, bowing of the legs, and short stature. The
current standard of care (SOC) therapy consists of multiple daily doses of oral
phosphate combined with appropriate doses of active vitamin D metabolites. SOC
therapy, when taken with a high degree of compliance and monitoring, can
improve the skeletal disease but often does not fully address the bone and
growth abnormalities nor does it target the pathophysiological cause of the
disease: renal phosphate wasting induced by high FGF23 levels. SOC therapy also
requires careful monitoring to avoid potential risks such as nephrocalcinosis,
hypercalciuria, and hyperparathyroidism. More efficacious, safer, and
convenient therapies clearly are needed.
KRN23 is a recombinant fully human monoclonal IgG1 antibody being developed to
treat XLH by binding and inhibiting FGF23 activity, thereby restoring normal
phosphate homeostasis. Four clinical studies have been conducted in adult
patients with XLH: a single dose Phase 1 safety and tolerability study of KRN23
(KRN23-US-02), a single dose Phase 1 safety and tolerability study of KRN23 in
Japan and Korea (KRN23-001), a repeat dose Phase 1/2 dose escalation study
(KRN23-INT-001), and an associated treatment extension study (KRN23 INT-002).
An additional open-label long-term extension study (UX023-CL203), a
double-blind, placebo-controlled, Phase 3 study (UX023-CL303), and an
open-label, paired bone biopsy Phase 3 study to evaluate changes in
osteomalacia at the tissue level with KRN23 treatment are ongoing. The safety
data from these studies have shown that KRN23 in single and repeated monthly
doses up to 1.0 mg/kg was well tolerated by adult XLH subjects. KRN23
sufficiently increased serum phosphorus levels, such that improvements in bone
physiology, structure and function would be expected. These data support the
initiation of further studies to evaluate the therapeutic benefit of KRN23 in
children who experience the most severe physical and health manifestations
associated with XLH. Currently, there are no approved treatments and a high
unmet medical need in pediatric XLH patients.
Adults and children with XLH have the same underlying defect but are at a
different stage of the disease. In childhood, normal phosphorus levels are
higher to promote bone formation, whereas in adults, the normal range is lower
coincident with reduced demand for bone formation. Therefore, smaller, more
frequent dosing may be preferred for pediatric hypophosphatemic patients to
maximize treatment effects without a plateau, drive serum phosphorus levels
closer to the normal range and minimize the troughs. This Phase 2 study will
examine the PD, efficacy and safety of KRN23 administered at multiple doses and
dose regimens in pediatric XLH patients.
The total treatment duration will vary by subject. The study will consist of an
individual dose Titration Period (16 weeks), a Treatment Period (48 weeks), and
a treatment extension period (up to 96 weeks), for a total treatment duration
of up to 160 weeks. For subjects that choose to end the study after Treatment
Extension Period I, Week 160 will be their end of study (EOS) efficacy visit
(referred to as EOS I). The study will also include a Treatment Extension
Period II (up to 56 weeks) to allow subjects to continue treatment until the
availability of a separate rollover study (or other mechanism of treatment) or
until September 2018, for a maximum total treatment duration of up to 216
weeks. Subjects who participate in Treatment Extension Period II will have an
EOS efficacy visit (referred to as EOS II). A safety follow-up telephone call
will occur at 5 weeks (+ 5 days) after the EOS (I or II) efficacy visit, and a
final safety visit will occur at 10 weeks (± 1 week) after the EOS (I or II)
efficacy visit for subjects that are not continuing on KRN23 treatment through
commercial use or another mechanism. The end of study is defined as the date of
the last protocol-specified procedures (including telephone contact) for the
last subject in the study. The dose response of KRN23 will be evaluated at 3
starting dose levels. Monthly (Q4) and biweekly (i.e., every other week; Q2)
dosing regimens will also be compared. KRN23 dosing will be individually
adjusted every 4 weeks as needed, according to serum phosphorus levels. The
goal is to achieve stable serum phosphorus levels in the target range, while
minimizing changes in the calcium control system. During Treatment Extension
Period I (and II, if applicable), all subjects will receive KRN23 at the Q2
dosing regimen. Data collected in this study will establish KRN23 dose and dose
regime for pediatric patients, and provide information about the PD, PK,
clinical efficacy and safety of KRN23 in children with XLH.
Study objective
The objectives of the study are to:
* Identify a dose and dosing regimen of KRN23, based on safety and PD effect,
in pediatric XLH patients
* Establish the safety profile of KRN23 for the treatment of children with XLH
including ectopic mineralization risk, cardiovascular effects, and
immunogenicity profile
* Characterize the PK/PD of the KRN23 doses tested in the monthly (Q4) and
biweekly (Q2) dose regimens in pediatric XLH patients
* Determine the PD effects of KRN23 treatment on markers of bone health in
pediatric XLH patients
* Obtain a preliminary assessment of the clinical effects of KRN23 on bone
health and deformity, muscle strength, and motor function
* Obtain a preliminary assessment of the effects of KRN23 on patient-reported
outcomes, including pain, disability, and quality of life in pediatric XLH
patients
* Evaluate the long-term safety and efficacy of KRN23
Study design
STUDY DESIGN AND METHODOLOGY:
UX023-CL201 is a randomized, multicenter, open-label, dose finding Phase 2
study. The study will be conducted in prepubescent children aged 5-12 years
with XLH to assess the PD, efficacy, and safety of KRN23 administered via
subcutaneous (SC) injections monthly (Q4, 28 days) or biweekly (Q2, 14 days)
for up to 216 weeks until the availability of a rollover study (or other
mechanism of treatment) or until September 2018. The study will consist of an
individual dose Titration Period (16 weeks), a Treatment Period (48 weeks), and
a Treatment Extension Period I (up to 96 weeks). Subjects may choose to end
participation in the study at Week 160 and complete an end of study (EOS)
efficacy visit (referred to as EOS I). For those subjects who choose to
continue after Week 160, the study will also include a Treatment Extension
Period II (up to 56 weeks) at the end of which subjects will have their EOS
efficacy visit (referred to as EOS II). A safety follow-up telephone call will
occur at 5 weeks (+ 5 days) after the EOS (I or II) efficacy visit, and a final
safety visit will occur at 10 weeks (± 1 week) after the EOS (I or II) efficacy
visit for subjects that are not continuing on KRN23 treatment through
commercial use or another mechanism. The end of study is defined as the date of
the last protocol-specified procedures (including telephone contact) for the
last subject in the study.
The study initially enrolled 36 pediatric subjects with XLH and radiographic
evidence of bone disease (pre-expansion subjects). The study was expanded to
include additional subjects who were required to have a level of rickets
severity of at least 1.5 points at the knee as defined by the Rickets Severity
Score (RSS) method for a total of approximately 50 subjects overall. All
subjects will discontinue oral phosphate and vitamin D metabolite therapy prior
to randomization and throughout the duration of the study.
There will be 3 cohorts in this study (n = 10 in cohorts 1 and 2 [pre-expansion
subjects] and n = 30 in cohort 3 [comprising both pre-expansion and expansion
subjects]); each with a Q4 and Q2 dosing group. Subjects will be randomized 1:1
to the KRN23 Q4 or Q2 dosing regimens within each cohort; randomization will be
stratified on subject gender. In order to maintain a level of gender balance,
no more than 20 patients of either sex can be enrolled in the in the
pre-expansion group. No requirement for gender balance will be applied in the
expansion group. The cohorts will be enrolled sequentially. The first cohort
will examine the lowest starting doses (0.2 mg/kg Q4 and 0.1 mg/kg Q2) and will
be enrolled first. As an added precautionary measure in this pediatric
population, the second cohort (0.4 mg/kg Q4 and 0.2 mg/kg Q2) cannot begin
dosing until the fourth subject in the first cohort completes the Week 4 visit.
The third cohort will be administered the highest starting doses (0.6 mg/kg Q4
and 0.3 mg/kg Q2).
DOSING DURING THE TITRATION PERIOD (Weeks 0-16)
The initial 16-week Titration Period is intended to identify the KRN23 dose
required to achieve the target peak PD effect. The goal is to identify an
individualized KRN23 dose that maintains serum phosphorus levels in the target
range. The target fasting serum phosphorus range for this study is 3.5- 5.0
mg/dL (1.13-1.62 mmol/L), based on the peak PD effect of KRN23. The dose will
be adjusted every 4 weeks, as needed, based on 2-week post-dose (peak) fasting
serum phosphorus levels.
At the end of the Titration Period, the population of 50 subjects will consist
of essentially two groups of 25 subjects, each with individually optimized
dosing of KRN23 at either a Q4 week or Q2 week frequency. Analyses of safety
and available PD and efficacy data are planned at the end of the Titration
Period (Week 16) and at Week 24 for pre-expansion subjects. Further analyses in
the pre-expansion group alone and for the overall population are planned at
Week 40 and at Week 64 at the end of the Treatment Period to compare treatment
outcomes to baseline (pre-dose). Analyses of long-term safety and efficacy will
be conducted during and at the completion of the Treatment Extension Period.
For more information, please refer to protocol synopsis.
Intervention
Bi-weekly of monthly injection with KRN23
Study burden and risks
For the most recent information on the burden, risks and benefits associated
with participation, please refer to section 5.3 of the protocol (*Summary of
Overall Risks and Potential Benefits*).
Leveroni Court 60
Novato, CA 94949
US
Leveroni Court 60
Novato, CA 94949
US
Listed location countries
Age
Inclusion criteria
1) Male or female, aged 5 * 12 years, inclusive, with open growth plates
2) Tanner stage of 2 or less based on breast and testicular development (assessed only in children * 8 years of age)
3) Diagnosis of XLH supported by ONE of the following:
- Confirmed PHEX mutation in the patient or a directly related family member with appropriate X-linked inheritance
- Serum iFGF23 level > 30 pg/mL by Kainos assay
4) Biochemical findings associated with XLH including:
- Serum phosphorus * 2.8 mg/dL (0.904 mmol/L)[criteria to be determined based on overnight fasting (min. 4 hours) values collected at SV2]
- Serum creatinine within age-adjusted normal range [criteria to be determined based on overnight fasting (min. 4 hours) values collected at SV2]
5) Standing height <50th percentile for age and gender using local normative data
6) Radiographic evidence of active bone disease including rickets in the wrists and/or knees, AND/OR, for expansion subjects, a RSS score in the knee of at least 1.5 points as determined by central read
7) Willing to provide access to prior medical records for the collection of historical growth, biochemical and radiographic data, and disease history.
8) Provide written or verbal assent (if possible) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures
9) 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.
10) Females who have reached menarche must have a negative pregnancy test at Screening and undergo additional pregnancy testing during the study. If sexually active, male and female subjects must be willing to use two highly effective methods of contraception for the duration of the study.
Exclusion criteria
1) Use of a pharmacologic vitamin D metabolite or analog (e.g. calcitriol, doxercalciferol, and paricalcitol) within 14 days prior to Screening Visit 2; washout will take place during the Screening Period
2) Use of oral phosphate within 7 days prior to Screening Visit 2; washout will take place during the Screening Period
3) Use of aluminum hydroxide antacids (e.g. Maalox® and Mylanta®), systemic corticosteroids, and thiazides within 7 days prior to Screening Visit 1
4) Use of growth hormone from 1 year to 3 months prior Screening Visit 1
5) Use of bisphosphonates for 6 months or more in the 2 years prior to Screening Visit 1
6) Presence of nephrocalcinosis on renal ultrasound graded * 3 based on the following scale:
0 = Normal
1 = Faint hyperechogenic rim around the medullary pyramids
2 = More intense echogenic rim with echoes faintly filling the entire pyramid
3 = Uniformly intense echoes throughout the pyramid
4 = Stone formation: solitary focus of echoes at the tip of the pyramid
7) Planned or recommended orthopedic surgery, including staples, 8-plates or osteotomy, within the clinical trial period
8) Hypocalcemia or hypercalcemia, defined as serum calcium levels outside the age-adjusted normal limits [means criteria to be determined based on overnight fasting (min. 4 hours) values collected at SV2]
9) Evidence of tertiary hyperparathyroidism as determined by the Investigator
10) Use of medication to suppress PTH (e.g. Sensipar®, cinacalcet) within 2 months prior to Screening Visit 1
11) 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.
12) Presence of a concurrent disease or condition that would interfere with study participation or affect safety
13) Positive for human immunodeficiency virus antibody, hepatitis B surface antigen, and/or
hepatitis C antibody
14) History of recurrent infection or predisposition to infection, or of known immunodeficiency
15) Use of a therapeutic monoclonal antibody within 90 days prior to Screening Visit 1 or history of allergic or anaphylactic reactions to any monoclonal antibody
16) Presence or history of any hypersensitivity to KRN23 excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects.
17) Use of any 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-000406-35-NL |
| CCMO | NL48635.042.14 |