E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Tumor Lysis Syndrome results from the rapid killing of a large quantity of tumor cells which occurs most often after the start of chemotherapy in patients with hematologic cancers. |
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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 | 16.0 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045152 |
E.1.2 | Term | Tumor 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 |
The primary objective of this trial is to compare the efficacy of Febuxostat with Allopurinol, in terms of sUA level control and preservation of renal function after seven days of treatment (Day 8) starting from 2 days prior to chemotherapy (Day 1). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are: •To compare the efficacy of Febuxostat with Allopurinol, in terms of: -maintenance of sUA levels < 7.5 mg/dL -occurrence of LTLS according to Cairo-Bishop criteria (see study protocol Appendix I, section 13.1) -occurrence of CTLS according to Cairo-Bishop criteria (see study protocol Appendix I, section 13.1) •To compare the safety of Febuxostat with Allopurinol.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Male or female patients a. aged ≥ 18 years, and b. scheduled for first cytotoxic chemotherapy cycle, regardless of the line of treatment, because of hematologic malignancies, and c. at intermediate or high risk of TLS (see Appendix II, section 13.2 of study protocol for risk stratification), and d. with sUA levels < 10 mg/dL at randomization (Visit 1), and e. candidate to Allopurinol treatment or have no access to Rasburicase. 2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3. 3. Female of childbearing potential may be enrolled providing a negative pregnancy test at screening and using a highly effective method of birth control resulting in a low failure rate (i.e. less than 1% per year). 4. Able to give written informed consent before any study related procedure. 5. Able to attend all the visits scheduled in the study. 6. Life expectancy > 1 months.
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E.4 | Principal exclusion criteria |
1. Patients known to be hypersensitive to Febuxostat or Allopurinol or to any of the components of the formulations. 2. Patients with hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactase malabsorption. 3. Patients with uncontrolled ischemic heart disease or congestive heart failure (CHF). 4. Pregnant or breast feeding women. 5. Patients with sUA levels ≥ 10 mg/dL at randomization (Visit 1). 6. Patients receiving Febuxostat, Allopurinol or any other urate lowering therapy (e.g. Rasburicase, probenecid) within 30 days prior to randomization. 7. Patients receiving mercaptopurine and azathioprine within 14 days prior to randomization. 8. High risk patients NOT candidate to Allopurinol treatment. 9. Patients with severe renal insufficiency. 10. Patients with severe hepatic insufficiency. 11. Patients with diagnosis of LTLS or CTLS at randomization (Visit 1). 12. Patients with any serious concomitant illness which, in the opinion of the Investigator, is incompatible with the protocol. 13. Patients receiving any other investigational agent within 30 days prior to randomization (Visit 1).
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy analysis will be based on the following co-primary endpoints: • Area under the curve of sUA from baseline (Day 1) to the evaluation visit (Day 8) (AUC sUA 1-8). • Change in serum creatinine level from baseline (Day 1) to the evaluation visit (Day 8).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
from baseline (Day 1) to the evaluation visit (Day 8) |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints are: • Assessment of treatment responder rate, where treatment response is defined as the maintenance of sUA ≤ 7.5 mg/dL from the start of chemotherapy (Day 3) to the evaluation visit (Day 8); treatment failure is defined as the presence of two or more consecutive values of sUA missing or > 7.5 mg/dL. The assessment will be based on the central laboratory result. • Assessment of LTLS, from start of chemotherapy (Day 3) to the evaluation visit (Day 8) based on local laboratory results. According to Cairo-Bishop definition LTLS is defined by the presence of 2 or more laboratory abnormalities including: a 25% increase or levels above normal for serum uric acid, potassium, and phosphate or a 25% decrease or levels below normal for calcium. For details, please refer to appendix 13.1.of the study protocol. • Assessment of CTLS, from start of chemotherapy (Day 3) to the evaluation visit (Day 8). According to Cairo-Bishop definition, CTLS is defined by the presence of LTLS in addition to 1 or more of the following significant clinical complications: renal insufficiency, cardiac arrhythmias, sudden death and seizures. The grade of CTLS is defined by the maximal grade of the clinical manifestation. For details, please refer to appendix 13.1.of the study protocol.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
from start of chemotherapy (Day 3) to the evaluation visit (Day 8) |
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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 | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
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
| 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 |
Brazil |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Poland |
Romania |
Russian Federation |
Serbia |
Spain |
Ukraine |
Croatia |
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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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last follow up visit of the last patient |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |