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| ID | Type | Description | Link |
|---|---|---|---|
| 2012-000776-42 | EudraCT Number |
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The purpose of this study is to determine whether febuxostat is superior to allopurinol in the prevention of tumor lysis syndrome (TLS) in patients with hematological malignancies at intermediate or high risk of TLS (according to Cairo-Bishop classification) who undergo chemotherapy
This study is designed as a randomised, double-blind, active-controlled, parallel-group study to be conducted in approximately 80 sites.
Approximately 340 male or female patients aged 18 or older suffering from hematologic malignancies (de novo patients or relapsing patients) at intermediate to high risk of TLS and scheduled for receiving the first cycle of cytotoxic chemotherapy, regardless of the line of treatment, will be randomized in this study. Eligible patients (as per screening visit) will be randomly allocated in a 1:1 ratio to Febuxostat or Allopurinol. The double-blind treatment period starts two days prior to the planned beginning of chemotherapy and continues for 7 to 9 consecutive days, according to Investigator judgment and on the basis of the actual duration of chemotherapy regimen administered to the patient. Along the study treatment, uric acid levels, creatinine levels, Laboratory TLS/Clinical TLS and Adverse Events represent the major clinical findings to be monitored on a daily basis. Overall the study encompasses 10 to 11 planned visits at site, including screening, randomisation, on treatment and final follow up visits.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Febuxostat | Experimental | Febuxostat for 7-9 days |
|
| Allopurinol | Active Comparator | Allopurinol for 7-9 days |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Febuxostat | Drug | Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Serum Uric Acid (sUA) Level Control | Area under the curve of sUA from baseline (Day 1) to the evaluation visit (Day 8) | 8 days |
| Preservation of Renal Function | Change in serum creatinine level from baseline (Day 1) to the evaluation visit (Day 8) | 8 days |
| Measure | Description | Time Frame |
|---|---|---|
| Treatment Responder Rate | Assessment of treatment responder rate, where treatment response is defined as the maintenance of sUA ≤ 7.5 mg/dL from Day 3 to Day 8 | 6 days |
| Assessment of Laboratory Tumor Lysis Syndrome (LTLS) |
| Measure | Description | Time Frame |
|---|---|---|
| Treatment Emergent Signs or Symptoms (TESS) | Incidence, severity, seriousness and treatment-causality of TESS | 14 ± 2 days |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michele Spina, MD | Centro Riferimento Oncologico (CRO) National Cancer Institute-Aviano-Italy | Principal Investigator |
| Angela Capriati, MD, PhD | Menarini Ricerche S.p.A. - Florence-Italy | Study Director |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26216382 | Derived | Spina M, Nagy Z, Ribera JM, Federico M, Aurer I, Jordan K, Borsaru G, Pristupa AS, Bosi A, Grosicki S, Glushko NL, Ristic D, Jakucs J, Montesinos P, Mayer J, Rego EM, Baldini S, Scartoni S, Capriati A, Maggi CA, Simonelli C; FLORENCE Study Group. FLORENCE: a randomized, double-blind, phase III pivotal study of febuxostat versus allopurinol for the prevention of tumor lysis syndrome (TLS) in patients with hematologic malignancies at intermediate to high TLS risk. Ann Oncol. 2015 Oct;26(10):2155-61. doi: 10.1093/annonc/mdv317. Epub 2015 Jul 27. |
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Subjects complying with inclusion/exclusion criteria were to be randomised to receive (blinded) standard, low or high dose of study treatment as per investigator's assessment (mainly based on renal function). Randomization was balanced by TLS risk and serum uric acid levels (≤ or > 7.5 mg/dL)
First patient in (screening) 01 Oct 2012, last patient out 11 Oct 2013. At 79 sites across 11 European countries (Croatia, Czech Republic, Germany, Hungary, Italy, Poland, Romania, Russia, Serbia, Spain and Ukraine) and Brazil
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| ID | Title | Description |
|---|---|---|
| FG000 | Febuxostat | Febuxostat for 7-9 days Febuxostat: Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion) |
| FG001 | Allopurinol | Allopurinol for 7-9 days Allopurinol: Standard dose, low dose or high dose (as per investigator's judgement at the time of randomization) from DAY 1 to DAY 7 (can be continued up to DAY 9 at investigator's discretion) |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Febuxostat | Febuxostat for 7-9 days Febuxostat: Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion) |
| BG001 | Allopurinol |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Serum Uric Acid (sUA) Level Control | Area under the curve of sUA from baseline (Day 1) to the evaluation visit (Day 8) | Intention to treat (ITT), defined as all randomized patients. Sample size calculation: at least an absolute reduction of 100 mg x h/dL for the AUCsUA1-8 in favour of febuxostat; 340 patients were sufficient to achieve approximately 80% power. Imputation method: last observation carried forward (LOCF); missing baseline values were not replaced. | Posted | Mean | Standard Deviation | mg x hour/dL | 8 days |
|
14 ± 2 days
Analysed for the Safety Population (all patients who received the study drug)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Febuxostat | Febuxostat for 7-9 days Febuxostat: Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Angela Capriati, Corporate Clinical Research Director | Menarini Ricerche S.p.A. | +39 055 5680 | 9933 | acapriati@menarini-ricerche.it |
| ID | Term |
|---|---|
| D015275 | Tumor Lysis Syndrome |
| D007938 | Leukemia |
| D008223 | Lymphoma |
| ID | Term |
|---|---|
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
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| ID | Term |
|---|---|
| D000069465 | Febuxostat |
| D000493 | Allopurinol |
| ID | Term |
|---|---|
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D001393 | Azoles |
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| Allopurinol | Drug | Standard dose, low dose or high dose (as per investigator's judgement at the time of randomization) from DAY 1 to DAY 7 (can be continued up to DAY 9 at investigator's discretion) |
|
|
Assessment of LTLS, from Day 3 to Day 8. 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.
| 6 days |
| Assessment of Clinical Tumor Lysis Syndrome (CTLS) | Assessment of CTLS, from Day 3 to 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 | 6 days |
| Protocol Violation |
|
| Patient refused to attend last visit |
|
Allopurinol for 7-9 days
Allopurinol: Standard dose, low dose or high dose (as per investigator's judgement at the time of randomization) from DAY 1 to DAY 7 (can be continued up to DAY 9 at investigator's discretion)
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| serum uric acid (sUA) | Number | participants |
|
| TLS risk | Number | participants |
|
| Type of Hematologic Malignancy | Number | participants |
|
Allopurinol for 7-9 days Allopurinol: Standard dose, low dose or high dose (as per investigator's judgement at the time of randomization) from DAY 1 to DAY 7 (can be continued up to DAY 9 at investigator's discretion) |
|
|
|
| Primary | Preservation of Renal Function | Change in serum creatinine level from baseline (Day 1) to the evaluation visit (Day 8) | ITT. Sample size calculation: no change in mean serum creatinine level from baseline to the end of treatment for febuxostat group while allopurinol has a increase of 13%; 340 patients were sufficient to achieve approximately 80% power. Imputation method: LOCF; missing baseline values were not replaced | Posted | Mean | Standard Deviation | change % | 8 days |
|
|
|
|
| Secondary | Treatment Responder Rate | Assessment of treatment responder rate, where treatment response is defined as the maintenance of sUA ≤ 7.5 mg/dL from Day 3 to Day 8 | Intention to Treat (ITT; no imputation applied | Posted | Number | % of patients who fail to respond | 6 days |
|
|
|
|
| Secondary | Assessment of Laboratory Tumor Lysis Syndrome (LTLS) | Assessment of LTLS, from Day 3 to Day 8. 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. | ITT; no imputation applied | Posted | Number | % of patients with LTLS occurrence | 6 days |
|
|
|
|
| Secondary | Assessment of Clinical Tumor Lysis Syndrome (CTLS) | Assessment of CTLS, from Day 3 to 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 | ITT; no imputation applied | Posted | Number | % of patients with CTLS occurrence | 6 days |
|
|
|
|
| Other Pre-specified | Treatment Emergent Signs or Symptoms (TESS) | Incidence, severity, seriousness and treatment-causality of TESS | Not Posted | 14 ± 2 days |
| 21 |
| 173 |
| 116 |
| 173 |
| EG001 | Allopurinol | Allopurinol for 7-9 days Allopurinol: Standard dose, low dose or high dose (as per investigator's judgement at the time of randomization) from DAY 1 to DAY 7 (can be continued up to DAY 9 at investigator's discretion) | 6 | 173 | 112 | 173 |
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Atrial Fibrillation | Cardiac disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Cardiac failure acute | Cardiac disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Myocardial ischaemia | Cardiac disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Bronchitis | Infections and infestations | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Septic shock | Infections and infestations | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Platelet count decreased | Investigations | MedDRA (Unspecified) | Non-systematic Assessment |
|
| White blood cell count decreased | Investigations | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Hypovolaemia | Metabolism and nutrition disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Tumour lysis syndrome | Metabolism and nutrition disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Cerebral ischaemia | Nervous system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Haematuria | Renal and urinary disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Renal failure | Renal and urinary disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Shock | Vascular disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Mucosal inflammation | General disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Platelet count decreased | Investigations | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Hyperphosphataemia | Metabolism and nutrition disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
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| D007154 | Immune System Diseases |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006573 |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |