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Febuxostat

Allopurinol

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Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion)

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)

Michele Spina, MD

Angela Capriati, MD, PhD

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.

Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies

Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies: a Randomized, Double Blind, Phase III Study Versus Allopurinol

Incidence, severity, seriousness and treatment-causality of TESS

Area under the curve of sUA from baseline (Day 1) to the evaluation visit (Day 8)

Change in serum creatinine level from baseline (Day 1) to the evaluation visit (Day 8)

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

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.

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

Menarini Group

Analysed for the Safety Population (all patients who received the study drug)

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)

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)

Total

Age, Continuous

Sex: Female, Male

< or = 7.5 mg/dL

> 7.5 mg/dL

serum uric acid (sUA)

Intermediate

High

TLS risk

Acute leukemia

Chronic lymphocytic leukemia

Type of Hematologic Malignancy

Dr. Angela Capriati, Corporate Clinical Research Director

Treatment, TLS risk (intermediate/high) and sUA level at baseline (≤ 7.5 mg/dL and \> 7.5 mg/dL) were inserted in the ANCOVA model as covariates

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.

Serum Uric Acid (sUA) Level Control

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies	NCT01724528	Tumor Lysis Syn...	Febuxostat Allopurinol	18 Years -	Menarini Group
Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies	NCT01724528	Tumor Lysis Syn...	Febuxostat Allopurinol	18 Years -	Menarini Group

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