Trial Outcomes & Findings for Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies (NCT NCT01724528)

NCT ID: NCT01724528

Last Updated: 2014-11-03

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 346 participants
• Primary outcome timeframe: 8 days
• Results posted on: 2014-11-03

Participant Flow

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

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)

Participant milestones

Measure	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)	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)
Overall Study STARTED	173	173
Overall Study COMPLETED	169	170
Overall Study NOT COMPLETED	4	3

Reasons for withdrawal

Measure	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)	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)
Overall Study Death	3	0
Overall Study Withdrawal by Subject	0	2
Overall Study Protocol Violation	0	1
Overall Study Patient refused to attend last visit	1	0

Baseline Characteristics

Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies

Baseline characteristics by cohort

Measure	Febuxostat n=173 Participants 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 n=173 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)	Total n=346 Participants Total of all reporting groups
Age, Continuous	58.5 years STANDARD_DEVIATION 14.26 • n=93 Participants	58.3 years STANDARD_DEVIATION 13.26 • n=4 Participants	58.4 years STANDARD_DEVIATION 13.75 • n=27 Participants
Sex: Female, Male Female	65 Participants n=93 Participants	67 Participants n=4 Participants	132 Participants n=27 Participants
Sex: Female, Male Male	108 Participants n=93 Participants	106 Participants n=4 Participants	214 Participants n=27 Participants
serum uric acid (sUA) < or = 7.5 mg/dL	151 participants n=93 Participants	152 participants n=4 Participants	303 participants n=27 Participants
serum uric acid (sUA) > 7.5 mg/dL	22 participants n=93 Participants	21 participants n=4 Participants	43 participants n=27 Participants
TLS risk Intermediate	143 participants n=93 Participants	141 participants n=4 Participants	284 participants n=27 Participants
TLS risk High	30 participants n=93 Participants	32 participants n=4 Participants	62 participants n=27 Participants
Type of Hematologic Malignancy Acute leukemia	34 participants n=93 Participants	25 participants n=4 Participants	59 participants n=27 Participants
Type of Hematologic Malignancy Chronic lymphocytic leukemia	80 participants n=93 Participants	94 participants n=4 Participants	174 participants n=27 Participants
Type of Hematologic Malignancy Lymphoma	59 participants n=93 Participants	54 participants n=4 Participants	113 participants n=27 Participants

PRIMARY outcome

Timeframe: 8 days

Population: 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.

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

Outcome measures

Measure	Febuxostat n=172 Participants 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 n=172 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)
Serum Uric Acid (sUA) Level Control	514.0 mg x hour/dL Standard Deviation 225.71	708.0 mg x hour/dL Standard Deviation 234.42

PRIMARY outcome

Timeframe: 8 days

Population: 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

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

Outcome measures

Measure	Febuxostat n=173 Participants 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 n=171 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)
Preservation of Renal Function	-0.83 change % Standard Deviation 26.977	-4.92 change % Standard Deviation 16.695

SECONDARY outcome

Timeframe: 6 days

Population: Intention to Treat (ITT; no imputation applied

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

Outcome measures

Measure	Febuxostat n=173 Participants 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 n=173 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)
Treatment Responder Rate	1.7 % of patients who fail to respond	4.0 % of patients who fail to respond

SECONDARY outcome

Timeframe: 6 days

Population: ITT; no imputation applied

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.

Outcome measures

Measure	Febuxostat n=173 Participants 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 n=173 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)
Assessment of Laboratory Tumor Lysis Syndrome (LTLS)	8.1 % of patients with LTLS occurrence	9.2 % of patients with LTLS occurrence

SECONDARY outcome

Timeframe: 6 days

Population: ITT; no imputation applied

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

Outcome measures

Measure	Febuxostat n=173 Participants 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 n=173 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)
Assessment of Clinical Tumor Lysis Syndrome (CTLS)	1.7 % of patients with CTLS occurrence	1.2 % of patients with CTLS occurrence

OTHER_PRE_SPECIFIED outcome

Timeframe: 14 ± 2 days

Incidence, severity, seriousness and treatment-causality of TESS

Outcome measures

Outcome data not reported

Adverse Events

Febuxostat

Serious events: 21 serious events

Other events: 116 other events

Deaths: 0 deaths

Allopurinol

Serious events: 6 serious events

Other events: 112 other events

Deaths: 0 deaths

Serious adverse events

Measure	Febuxostat n=173 participants at risk 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 n=173 participants at risk 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)
Blood and lymphatic system disorders Anaemia	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Blood and lymphatic system disorders Febrile neutropenia	1.7% 3/173 • Number of events 3 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Blood and lymphatic system disorders Leukopenia	1.2% 2/173 • Number of events 2 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Blood and lymphatic system disorders Neutropenia	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Cardiac disorders Atrial Fibrillation	1.2% 2/173 • Number of events 2 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Cardiac disorders Cardiac failure acute	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Cardiac disorders Myocardial ischaemia	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Gastrointestinal disorders Abdominal pain	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
General disorders Pyrexia	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Infections and infestations Bronchitis	0.58% 1/173 • Number of events 2 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Infections and infestations Pneumonia	2.9% 5/173 • Number of events 5 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	1.2% 2/173 • Number of events 2 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Infections and infestations Sepsis	1.7% 3/173 • Number of events 3 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Infections and infestations Septic shock	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Investigations Blood bilirubin increased	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Investigations Platelet count decreased	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Investigations White blood cell count decreased	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Metabolism and nutrition disorders Hypovolaemia	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Metabolism and nutrition disorders Tumour lysis syndrome	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Nervous system disorders Cerebral ischaemia	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Nervous system disorders Headache	1.2% 2/173 • Number of events 2 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Renal and urinary disorders Haematuria	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Renal and urinary disorders Renal failure	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Vascular disorders Hypotension	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Vascular disorders Shock	0.58% 1/173 • Number of events 1 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	0.00% 0/173 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)

Other adverse events

Measure	Febuxostat n=173 participants at risk 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 n=173 participants at risk 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)
Blood and lymphatic system disorders Anaemia	22.0% 38/173 • Number of events 48 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	14.5% 25/173 • Number of events 31 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Blood and lymphatic system disorders Leukopenia	14.5% 25/173 • Number of events 26 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	15.6% 27/173 • Number of events 27 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Blood and lymphatic system disorders Neutropenia	17.3% 30/173 • Number of events 32 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	23.1% 40/173 • Number of events 42 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Blood and lymphatic system disorders Thrombocytopenia	14.5% 25/173 • Number of events 28 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	11.0% 19/173 • Number of events 20 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Gastrointestinal disorders Constipation	8.1% 14/173 • Number of events 16 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	6.4% 11/173 • Number of events 12 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Gastrointestinal disorders Diarrhoea	9.2% 16/173 • Number of events 21 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	6.4% 11/173 • Number of events 13 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Gastrointestinal disorders Nausea	12.7% 22/173 • Number of events 25 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	12.1% 21/173 • Number of events 23 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Gastrointestinal disorders Vomiting	5.8% 10/173 • Number of events 11 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	6.9% 12/173 • Number of events 12 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
General disorders Mucosal inflammation	6.4% 11/173 • Number of events 11 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	1.7% 3/173 • Number of events 3 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
General disorders Pyrexia	13.3% 23/173 • Number of events 25 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	10.4% 18/173 • Number of events 21 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Investigations Platelet count decreased	5.2% 9/173 • Number of events 9 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	3.5% 6/173 • Number of events 6 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Metabolism and nutrition disorders Hyperglycaemia	3.5% 6/173 • Number of events 7 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	5.2% 9/173 • Number of events 10 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Metabolism and nutrition disorders Hyperphosphataemia	5.2% 9/173 • Number of events 9 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	2.3% 4/173 • Number of events 4 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)
Nervous system disorders Headache	7.5% 13/173 • Number of events 14 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)	2.9% 5/173 • Number of events 5 • 14 ± 2 days Analysed for the Safety Population (all patients who received the study drug)

Additional Information

Dr. Angela Capriati, Corporate Clinical Research Director

Menarini Ricerche S.p.A.

Phone: +39 055 5680

Email: acapriati@menarini-ricerche.it

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: LTE60