| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| XLF is a disorder of hyphophosphatemia,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 phosphorum levels lead to defective bone mineralization and consequently to rickets in children and osteomalacia in adults, the two major pathologic outcomes of the hyphophosphatemia |
| XLH è una malattia caratterizzata da ipofosfatemia, peridta di fosfati a livello renale e la più comune forma ereditabile di rachitismo. Nei pazienti XLH l'eccesso di FGF23 circolante mette in pericolo il riassorbimento di fosfati a livello renale. Bassi livelli sierici di fosforo cronico portano ad una mineralizzazione difettosa ossea e di conseguenza rachitismo nei bambini e osteomalacia negli adulti,i due principali risultati patologici della ipofosfatemia. |
|
| E.1.1.1 | Medical condition in easily understood language |
| inheritable form of rickets |
| Ereditabile forma di rachitismo. |
|
| 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 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Establish the effect of KRN23 treatment compared with increasing serum phosphorum levels in adults with XLH |
| Valutare l'effetto del trattamento con KRN 23 rispetto al placebo nell'aumentare i livelli di fosforo sierico in adulti con XLH |
|
| E.2.2 | Secondary objectives of the trial |
| The key secondary efficacy objective is to establish the effect of KRN23 treatment compared with placebo on skeletal pain associated with XLH. Other secondary efficay objectives are to establish the effect of KRN23 treatment compared with placebo in adults with XLH on: 1)additional PD markers reflecting the status of phosphate-calcium homeostasis and renal function 2)bone remodeling as assessed by biochemical markers of bone remodeling 3)Additional PROs assessing skeletal pain, stiffness,fatigue and physical health function |
| L'obiettivo di efficacia secondario più importante consiste nel valutare l'effetto del trattamento con KRN23 rispetto al placebo sul dolore scheletrico associato a XLH. Altri obiettivi di efficacia secondari sono valutare l'effetto del trattamento con KRN23rispetto al placebo in adulti con XLH su:1)Ulteriori marcatori di farmacodinamica che riflettono l'omeostasi fosfato-calcio e la funzione renale.2)Rimodellamento osseo valutato mediante marcatori biochimici di rimodellamento osseo.3)Ulteriori esiti riportati dal paziente riguardanti dolore scheletrico , rigidità, affaticamento e salute fisica. |
|
| 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 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 iFGF23 level > 30 pg/mL by Kainos assay
3) Biochemical findings consistent with XLH at Screening Visit 2 following overnight fasting (min. 8 hours):
• Serum phosphorus < 2.5 mg/dL (0.81 mmol/L)
• TmP/GFR of < 2.5 mg/dL
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 Visit 1. (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 Visit 2 with confirmation that the renal insufficiency is not due to nephrocalcinosis
6) If taking chronic pain medications (including narcotic pain medications/opioids), must be on a stable regimen for at least 21 days prior to Screening Visit 1, and be willing to maintain medications at the same stable dose(s) and schedule throughout the Placebo-controlled Treatment Period of the study. The dose must not exceed 60 mg oral morphine equivalents/day
7) Provide written informed consent or if a minor, provide written consent 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
8) Willing to provide access to prior medical records for the collection of biochemical and radiographic data and disease history
9) 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
10) Participants of child bearing potential or with partners of child-bearing potential who have not undergone a total hysterectomy or 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
11) 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
12) Must have completed at least 4 of 7 days of the patient diaries before the Baseline visit |
|
| 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 a pharmacologic vitamin D metabolite or analog (calcitriol, doxercalciferol, and paricalcitol) within 14 days prior to Screening Visit 2
2) Use of oral phosphate within 14 days prior to Screening Visit 2
3) Use of aluminum hydroxide antacids, acetazolamides, and thiazides within 7 days prior to Screening Visit 2
4) Chronic use of systemic corticosteroids defined as more than 10 days in the 2 months prior to Screening Visit 1
5) Corrected serum calcium level ≥ 10.8 mg/dL (2.7 mmol/L) at Screening Visit 2
6) Serum iPTH ≥ 2.5 upper limit of normal (ULN) at Screening Visit 1
7) Use of medication to suppress PTH (cinacalcet, for example) within 60 days prior to Screening Visit 1
8) Use of bisphosphonates in the 2 years prior to Screening Visit 1
9) Use of denosumab in the 6 months prior to Screening Visit 1
10) Use of teriparatide in the 2 months prior to Screening Visit 1
11) Planned or recommended orthopedic surgery within the first 24 weeks of the clinical trial period
12) History of traumatic fracture or orthopedic surgery within 6 months prior to Screening Visit 1
13) Use of KRN23, or any other therapeutic monoclonal antibody within 90 days prior to Screening Visit 1
14) Use of any investigational product or investigational medical device within 30 days prior to Screening Visit 1, 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
15) Pregnant or breastfeeding at Screening /Baseline or planning to become pregnant (self or partner) at any time during the study
16) Unable or unwilling to withhold prohibited medications throughout the study
17) 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
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 (other than dental abscesses, which are known to be associated with XLH) 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Il parametro di efficacia primario è la proporzione di soggetti che hanno raggiunto livelli di fosforo sierico al di sopra del limite inferiore della norma (lower limit of normal, LLN); 2,5 mg/dl [0,81 mmol/l]) a metà dell’intervallo di tempo tra le somministrazioni (ad esempio settimane 2, 6, 10, 14, 18 and 22), basandosi sulla media dei risultati di tutti i cicli effettuati tra il basale e la settimana 24. |
| The primary endpoint is the proportion of subjects achieving mean serum phosphorus levels above the lower limit of normal (LLN; 2.5 mg/dL [0.81 mmol/L]) at the mid-point of the dose interval (i.e., Weeks 2, 6, 10, 14, 18 and 22), as averaged across dose cycles between baseline and Week 24. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| weeks 2, 6, 10, 14, 18, 22 e 24 |
| Settimane 2, 6, 10, 14, 18, 22 e 24 |
|
| E.5.2 | Secondary end point(s) |
| Key Secondary Efficacy Endpoint: • Change from baseline in BPI Q3 (Worst Pain) score at Week 24 as averaged from daily assessments recorded over 1 week Additional Secondary Efficacy Endpoints: • 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 and percent change from baseline over time in serum 1,25(OH)2D, urinary phosphorus, ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR), and tubular reabsorption of phosphate (TRP) • Change and percent change from baseline over time in biochemical markers of bone remodeling, including procollagen type 1 N-propeptide (P1NP), carboxy-terminal cross-linked telopeptide of type I collagen (CTx), and bone-specific alkaline phosphatase (BALP) will be assessed in serum • Change from baseline in BPI Pain Severity and in Pain Interference scores over time • Change from baseline in Brief Fatigue Inventory (BFI) Severity and Interference scores over time • Change from baseline to Week 24 in the Stiffness and Physical Function domains of the Western Ontario and McMaster University Osteoarthritis Index (WOMAC®) |
| Parametro di efficacia secondario: • Variazione rispetto al basale del punteggio della domanda del BPI-Q3(Peggior dolore) alla settimana 24, basandosi sulla media dei risultati giornalieri registrati inuna settimana. Ulteriori parametri di efficacia secondari: • Ulteriori misurazioni per valutare i livelli di fosforo sierico tra il basale e la visita 24 includono: o La proporzione di soggetti che ha raggiunto valori medi di fosforo sierico al di sopra del LLN (2,5 mg/dl [0,81 mmol/l] alla fine del ciclo di somministrazione (a 4 settimane dalla somministrazione), basandosi sulla media dei valori registrati in tutti i cicli. o Punto di mezzo del ciclo di somministrazione: variazione media rispetto al basale e variazione percentuale rispetto al basale, basandosi sulla media dei valori registrati in tutti i cicli. o Fine del ciclo di somministrazione: variazione media rispetto al basale e variazione percentuale rispetto al basale, basandosi sulla media dei valori registrati in tutti i cicli. o Esposizione cumulativa: area sotto la curva (Area Under the Curve, AUC). • Variazione e variazione percentuale rispetto al basale nel corso del tempo del 1,25(OH)2D sierico, fosforo urinario, rapporto tra il riassorbimento tubulare massimo di fosfato e il tasso di filtrazione glomerulare (TmP/GFR), e riassorbimento tubulare di fosfato (tubular reabsorption of phosphate, TRP). • Saranno misurate nel siero la variazione e la variazione percentuale, nel tempo rispetto al basale dei marcatori biochimici di rimodellamento del tessuto osseo, compresi il propeptide N-terminale del collagene di tipo 1 (procollagen type 1 N-propeptide, P1NP), il telopeptide C-terminale del Collagene di tipo I (CTx) e la fosfatasi alcalina specifica per il tessuto osseo (bone-specific alkaline phosphtase, BALP). • Variazione nel tempo rispetto al basale dei punteggi nel BPI Intensità del Dolore, e nel Dolore Interferenza. • Variazione nel tempo rispetto al basale dei punteggi di intensità e interferenza nel questionario per la valutazione della stanchezza cronica (BFI) . • Variazione dal basale alla settimana 24 nelle aree della rigidità e dell’attività fisica del Western Ontario and McMaster University Osteoarthritis Index (WOMAC®) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| BPI Q3 - baseline and week 24 Serum phosphorus - baseline and week 24 1,25(OH)2D - Urinary phosphorus TmP/GFR TRP P1NP CTx BALP BPI Pain severity BFI WOMAC - baseline and week 24 |
| BPI Q3 - basale e settimana 24 Fosforo sierico - basale e settimana 24 1,25(OH)2D - Fosforo urinario TmP/GFR TRP P1NP CTx BALP BPI Pain severity BFI WOMAC - basale e settimana 24 |
|
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 | No |
| 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 |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 17 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 17 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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