E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
XLH is a disorder of hypophosphatemia, renal phosphate wasting, and the most common inheritable form of rickets. In XLH patients, excess circulating fibroblast growth factor (FGF23) impair phosphate reabsorption in the kidney. Chronic low serum phosphorus levels lead to defective bone mineralization and, consequently, to rickets in children and osteomalacia in adults, the two major pathologic outcomes of the hypophosphatemia. |
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E.1.1.1 | Medical condition in easily understood language |
Inheritable form of rickets |
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E.1.1.2 | Therapeutic area | Body processes [G] - Bones and nerves physological processes [G11] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10016206 |
E.1.2 | Term | Familial hypophosphataemic rickets |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Establish the effect of KRN23 treatment on improvement in XLH-associated osteomalacia as determined by the following histomorphometric indices
· Osteoid Thickness (O.Th)
· Osteoid surface/Bone surface (OS/BS)
· Osteoid volume/Bone volume (OV/BV)
· Mineralization lag time (MLt)
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E.2.2 | Secondary objectives of the trial |
The key secondary efficacy objective is to establish the effect of KRN23 treatment on
increasing serum phosphorus levels in adults with XLH. Other secondary efficacy objectives are to establish the effect of KRN23 treatment in adults with XLH on:
· Changes from baseline in parameters of bone mineralization including mineral apposition rate (MAR), mineralizing surface (MS/BS), bone formation rate (BFR),
and others
· Additional PD markers reflecting the status of phosphorus homeostasis and renal
function
· Bone remodeling as assessed by bone turnover markers
· PROs assessing skeletal pain and fatigue |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Individuals eligible to participate in this study must meet all of the following criteria:
1) Male or female, aged 25 - 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 the patient or a directly related family
member with appropriate X-linked inheritance
· Serum 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 45-60 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
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 bilateral salpingo-oophorectomy and are sexually active must consent to use an effective method 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 |
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E.4 | Principal exclusion criteria |
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:
1) Use of any pharmacologic vitamin D metabolite or analog (e.g. calcitriol,
doxercalciferol, and paricalcitol) within the 2 years prior to Screening
2) Use of oral phosphate within the 2 years prior to Screening
3) Use of aluminum hydroxide antacids, acetazolamides, and thiazides within 7 days
prior to Screening
4) Use of oral bisphosphonates for 6 months or more in the 2 years prior to Screening
5) Chronic use of systemic corticosteroids defined as more than 10 days in the 2 months prior to Screening
6) Corrected serum calcium level ≥ 10.8 mg/dL (2.7 mmol/L) at Screening
7) Serum iPTH ≥ 1.5 times the upper limit of normal (ULN) at Screening
8) Use of medication to suppress PTH (cinacalcet for example) within 60 days prior to
Screening
9) Prothrombin time/Partial thromboplastin time (PT/PTT) outside the normal range at Screening
10) 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
11) Pregnant or breastfeeding at Screening or planning to become pregnant (self or
partner) at any time during the study
12) Unable or unwilling to withhold prohibited medications throughout the study
13) Documented dependence on narcotics
14) Use of KRN23, or any other therapeutic monoclonal antibody within 90 days prior to Screening
15) 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.
16) 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
17) History of allergic reaction or adverse reactions to tetracycline
18) Prior history of positive test for human immunodeficiency virus antibody, hepatitis B surface antigen, and/or hepatitis C antibody
19) History of recurrent infection or predisposition to infection, or of known
immunodeficiency
20) Presence of malignant neoplasm (except basal cell carcinoma)
21) Presence of a concurrent disease or condition that would interfere with study
participation or affect safety
22) 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the percent change from baseline in excess osteoid based on analysis of iliac crest bone biopsies after 48 weeks of KRN23 treatment using the following histomorphometric indices:
· O.Th
· OS/BS
· OV/BV
· MLt
The primary analysis will be performed using the primary analysis set. Histomorphometric indices of O.Th, OS/BS, OV/BV and MLt at baseline, end of study, and their percent change from baseline at end of study will be summarized.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoint is the proportion of subjects achieving mean serum phosphorus levels above the LLN (2.5 mg/dL [0.81 mmol/L]) 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. The secondary efficacy endpoints will compare the effects of treatment with KRN23 on changes in:
· MAR, MS/BS, BFR and additional measures of bone formation and remodeling
· Additional measures to assess serum phosphorus levels between baseline and Week
24 include:
o Proportion of subjects achieving mean serum phosphorus levels above the
LLN (2.5 mg/dL [0.81 mmol/L] at the end of the dosing cycle (4 weeks after
dosing), as averaged across dose cycles
o Mid-point of dosing cycle: mean change from baseline, and percent change
from baseline averaged across dose cycles
o End of dosing cycle: mean change from baseline, and percent change from
baseline averaged across dose cycles
o Cumulative exposure: area under the curve (AUC)
· Change from baseline over time in serum 1,25(OH)2D, urinary phosphorus,
TmP/GFR, and TRP
Change and percent change from baseline over time in serum bone turnover markers,
including P1NP, CTx-I, and BALP
Additional analyses of serum phosphorus including observed values, change from baseline,
percent change from baseline over time, and area under the curve will be summarized.
Similar descriptive analyses will be performed for 1,25(OH)2D, urinary phosphorus,
TmP/GFR, and TRP. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Bone biopsies after 48 weeks
Serum phosphorus - Weeks 2, 6, 14, and 22
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Denmark |
France |
Ireland |
Netherlands |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 12 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 12 |