E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hematological malignancies at intermediate to high risk of Tumor Lysis Syndrome ( TLS) prevention. |
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E.1.1.1 | Medical condition in easily understood language |
Tumore Lysis Syndrome ( TLS) results from the rapid killing of a large quantity of tumor cells which occurs most often after the start of Chemotherapy in patients with haematologic cancer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10045170 |
E.1.2 | Term | Tumour lysis syndrome |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 |
-To assess the pharmacokinetics (PK) of febuxostat in paediatric patients (≥6<18 years of age) and in adults suffering from hematological malignancies at intermediate to high risk of TLS. -To compare the febuxostat exposure in pediatric patients (≥6<18 years of age) with the one achieved in adults administered with a dose of 120 mg/QD.
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E.2.2 | Secondary objectives of the trial |
-To compare the pharmacodynamics (PD) of febuxostat between pediatric patients (≥6<18 years of age) and adults. -To evaluate and compare the PK/PD relationship of febuxostat in pediatric patients (≥6<18 years of age) and adults. -To evaluate the safety of febuxostat between pediatric patients (≥6<18 years of age) and adults. -To evaluate the occurrence of Laboratory TLS (LTLS) and Clinical TLS (CTLS) according to Cairo and Bishop Criteria -To assess the age-appropriate formulation acceptability in children. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients meeting ALL the following criteria will be eligible to enter the study:
1.male and female children of 6 to less than 12 years of age, adolescents of 12 to less than 18 years of age, and adults: a.scheduled for first cytotoxic chemotherapy cycle, regardless of the line of treatment, because of hematologic malignancies, and b.at intermediate or high risk for TLS, and c.with serum uric acid (sUA) levels < 10 mg/dL at Visit 1 (Day 1), and d.with no access to rasburicase;
2.Karnofsky performance status (KPS) of 100 to 30 for patients aged 16 years and older; Lansky Play performance status (LPS) of 100 to 30 for patients aged less than 16 years;
3.A female of childbearing potential may be enrolled providing she: - has a negative pregnancy test during screening period and - is routinely using a highly effective method of birth control resulting in a failure rate of less than 1% per year when used consistently and correctly (e.g. combined [estrogen and progestogen containing] hormonal contraception associated with inhibition of ovulation [oral, intravaginal, transdermal], progestogen-only containing hormonal contraception associated with inhibition of ovulation [oral, injectable, implantable], intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or total sexual abstinence) until 6 months from the last study drug administration. ;
4.informed consent before any study-related procedures obtained by patient for adults or by patient’s parents (one or both according to local regulation) or legal guardian for children and adolescents;
5.life expectancy >1 month.
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E.4 | Principal exclusion criteria |
Patients will not be eligible to participate in the study if they meet ANY of the following exclusion criteria:
1.patients known to be hypersensitive to febuxostat or to any components of the formulation; 2.patients with hereditary problems of galactose intolerance, the lapp lactase deficiency, or glucose-galactase malabsorption; 3.pregnant or breastfeeding women; 4.patients receiving febuxostat or any other urate-lowering therapy (e.g. allopurinol, rasburicase, probenecid) within 30 days prior to Visit 1 (Day 1); 5.patients receiving mercaptopurine and azathioprine within 14 days prior to Visit 1 (Day 1); 6.patients with severe renal insufficiency; 7.patients with severe hepatic insufficiency; 8.patients with diagnosis of Laboratory TLS (LTLS) or Clinical TLS (CTLS) at Visit 1 (Day 1). 9.Patients receiving any other investigational agent within 30 days prior to study Visit 1 (Day 1). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Pharmacokinetic endpoints derived from the study will include: Primary PK parameters: CL/F, Vd/F and Ka. Derived PK parameters: AUC and Cmax.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Blood samples will be collected on Visits 2, 3, 4, 5, 6, 7 and 8 (i.e., after the first treatment administration and on each following visit until the Evaluation Visit). Four additional blood samples are required for each patient on Visit 7 (Day 7) at the selected sampling intervals: 0.5-2 hours, 2-4 hours, 4-6 hours and 6-8 hours post study drug intake. |
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E.5.2 | Secondary end point(s) |
Pharmacodynamic endpoint: 1. Area under the curve of sUA from baseline (Visit 1, Day 1) to the Evaluation Visit (Visit 8, Day 8) (AUC sUA 1-8) based on central laboratory results.
PK/PD endpoint: 2.The PK/PD relationship will be evaluated based on sUA levels and febuxostat exposure.
Clinical endpoints: 3. Incidence of Laboratory TLS (LTLS) from Start of Chemotherapy (Visit 3, Day 3) to the Evaluation Visit (Visit 8, Day 8), based on local laboratory results. -Incidence and grading of Clinical TLS (CTLS) from Start of Chemotherapy (Visit 3, Day 3) to the Evaluation Visit (Visit 8, Day 8) based on local laboratory results.
Safety endpoints: 4.Incidence, severity (both through Mild/Moderate/Severe scale and NCI-CTCAE grade), seriousness and treatment causality of Treatment-Emergent Signs and Symptoms (TESS). -Frequency of clinically significant abnormalities in physical examination, safety laboratory tests, vital signs and 12 Lead ECG. -Change in PS according to Karnofsky/Lansky scales.
5. Acceptability assessment of the age-appropriate formulation only for children. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Blood samples for sUA analysis will be performed from Visits 1 to 8 (i.e., before 1st drug intake, on each following visit until the Evaluation Visit). 2. PK/PD timepoints are the same of both primary endpoint and the pharmacodynamic timepoints. 3. From start of treatment (day 1) to the end of study visit 10 (day 14±2) 4. From start of chemotherapy (day 3) to evaluation visit (day 8) 5. From start of treatment (day 1) to visit 7 (day 7 ) or 9 (day 9) based on investigator's judgment.
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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 | No |
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 | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
To assess the PK and PD of febuxostat in pediatric patients (≥6<18 years of age). |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 5 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
Bulgaria |
Hungary |
Italy |
Spain |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |