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Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies (FLORENCE)

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ClinicalTrials.gov Identifier: NCT01724528
Recruitment Status : Completed
First Posted : November 9, 2012
Results First Posted : November 3, 2014
Last Update Posted : November 3, 2014
Sponsor:
Information provided by (Responsible Party):
Menarini Group

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Condition Tumor Lysis Syndrome
Interventions Drug: Febuxostat
Drug: Allopurinol
Enrollment 346
Recruitment Details 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
Pre-assignment Details 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)
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description

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)

Period Title: Overall Study
Started 173 173
Completed 169 170
Not Completed 4 3
Reason Not Completed
Death             3             0
Withdrawal by Subject             0             2
Protocol Violation             0             1
Patient refused to attend last visit             1             0
Arm/Group Title Febuxostat Allopurinol Total
Hide Arm/Group Description

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 of all reporting groups
Overall Number of Baseline Participants 173 173 346
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 173 participants 173 participants 346 participants
58.5  (14.26) 58.3  (13.26) 58.4  (13.75)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 173 participants 173 participants 346 participants
Female
65
  37.6%
67
  38.7%
132
  38.2%
Male
108
  62.4%
106
  61.3%
214
  61.8%
serum uric acid (sUA)  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 173 participants 173 participants 346 participants
< or = 7.5 mg/dL 151 152 303
> 7.5 mg/dL 22 21 43
TLS risk  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 173 participants 173 participants 346 participants
Intermediate 143 141 284
High 30 32 62
Type of Hematologic Malignancy  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 173 participants 173 participants 346 participants
Acute leukemia 34 25 59
Chronic lymphocytic leukemia 80 94 174
Lymphoma 59 54 113
1.Primary Outcome
Title Serum Uric Acid (sUA) Level Control
Hide Description Area under the curve of sUA from baseline (Day 1) to the evaluation visit (Day 8)
Time Frame 8 days
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description:

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)

Overall Number of Participants Analyzed 172 172
Mean (Standard Deviation)
Unit of Measure: mg x hour/dL
514.0  (225.71) 708.0  (234.42)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments 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
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares means difference
Estimated Value -196.794
Confidence Interval (2-Sided) 95%
-238.600 to -154.988
Estimation Comments [Not Specified]
2.Primary Outcome
Title Preservation of Renal Function
Hide Description Change in serum creatinine level from baseline (Day 1) to the evaluation visit (Day 8)
Time Frame 8 days
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description:

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)

Overall Number of Participants Analyzed 173 171
Mean (Standard Deviation)
Unit of Measure: change %
-0.83  (26.977) -4.92  (16.695)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments 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
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0903
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares means difference
Estimated Value 4.0970
Confidence Interval (2-Sided) 95%
-0.6467 to 8.8406
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Treatment Responder Rate
Hide Description 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
Time Frame 6 days
Hide Outcome Measure Data
Hide Analysis Population Description
Intention to Treat (ITT; no imputation applied
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description:

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)

Overall Number of Participants Analyzed 173 173
Measure Type: Number
Unit of Measure: % of patients who fail to respond
1.7 4.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1993
Comments [Not Specified]
Method Wilson's confidence interval
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.0231
Confidence Interval (2-Sided) 95%
-0.0153 to 0.0654
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Assessment of Laboratory Tumor Lysis Syndrome (LTLS)
Hide Description 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.
Time Frame 6 days
Hide Outcome Measure Data
Hide Analysis Population Description
ITT; no imputation applied
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description:

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)

Overall Number of Participants Analyzed 173 173
Measure Type: Number
Unit of Measure: % of patients with LTLS occurrence
8.1 9.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8488
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative risk
Estimated Value 0.875
Confidence Interval (2-Sided) 95%
0.4408 to 1.7369
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Assessment of Clinical Tumor Lysis Syndrome (CTLS)
Hide Description 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
Time Frame 6 days
Hide Outcome Measure Data
Hide Analysis Population Description
ITT; no imputation applied
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description:

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)

Overall Number of Participants Analyzed 173 173
Measure Type: Number
Unit of Measure: % of patients with CTLS occurrence
1.7 1.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative risk
Estimated Value 0.994
Confidence Interval (2-Sided) 95%
0.9691 to 1.0199
Estimation Comments [Not Specified]
6.Other Pre-specified Outcome
Title Treatment Emergent Signs or Symptoms (TESS)
Hide Description Incidence, severity, seriousness and treatment-causality of TESS
Time Frame 14 ± 2 days
Outcome Measure Data Not Reported
Time Frame 14 ± 2 days
Adverse Event Reporting Description Analysed for the Safety Population (all patients who received the study drug)
 
Arm/Group Title Febuxostat Allopurinol
Hide Arm/Group Description

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)

All-Cause Mortality
Febuxostat Allopurinol
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Febuxostat Allopurinol
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   21/173 (12.14%)      6/173 (3.47%)    
Blood and lymphatic system disorders     
Anaemia * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
Febrile neutropenia * 1  3/173 (1.73%)  3 1/173 (0.58%)  1
Leukopenia * 1  2/173 (1.16%)  2 0/173 (0.00%)  0
Neutropenia * 1  1/173 (0.58%)  1 1/173 (0.58%)  1
Thrombocytopenia * 1  0/173 (0.00%)  0 1/173 (0.58%)  1
Cardiac disorders     
Atrial Fibrillation * 1  2/173 (1.16%)  2 0/173 (0.00%)  0
Cardiac failure acute * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
Myocardial ischaemia * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
Gastrointestinal disorders     
Abdominal pain * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
General disorders     
Pyrexia * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
Infections and infestations     
Bronchitis * 1  1/173 (0.58%)  2 0/173 (0.00%)  0
Pneumonia * 1  5/173 (2.89%)  5 2/173 (1.16%)  2
Sepsis * 1  3/173 (1.73%)  3 0/173 (0.00%)  0
Septic shock * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
Investigations     
Blood bilirubin increased * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
Platelet count decreased * 1  1/173 (0.58%)  1 1/173 (0.58%)  1
White blood cell count decreased * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
Metabolism and nutrition disorders     
Hypokalaemia * 1  0/173 (0.00%)  0 1/173 (0.58%)  1
Hypovolaemia * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
Tumour lysis syndrome * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
Nervous system disorders     
Cerebral ischaemia * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
Headache * 1  2/173 (1.16%)  2 0/173 (0.00%)  0
Renal and urinary disorders     
Haematuria * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
Renal failure * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Pleural effusion * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
Respiratory failure * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
Vascular disorders     
Hypotension * 1  0/173 (0.00%)  0 1/173 (0.58%)  1
Shock * 1  1/173 (0.58%)  1 0/173 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (Unspecified)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Febuxostat Allopurinol
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   116/173 (67.05%)      112/173 (64.74%)    
Blood and lymphatic system disorders     
Anaemia * 1  38/173 (21.97%)  48 25/173 (14.45%)  31
Leukopenia * 1  25/173 (14.45%)  26 27/173 (15.61%)  27
Neutropenia * 1  30/173 (17.34%)  32 40/173 (23.12%)  42
Thrombocytopenia * 1  25/173 (14.45%)  28 19/173 (10.98%)  20
Gastrointestinal disorders     
Constipation * 1  14/173 (8.09%)  16 11/173 (6.36%)  12
Diarrhoea * 1  16/173 (9.25%)  21 11/173 (6.36%)  13
Nausea * 1  22/173 (12.72%)  25 21/173 (12.14%)  23
Vomiting * 1  10/173 (5.78%)  11 12/173 (6.94%)  12
General disorders     
Mucosal inflammation * 1  11/173 (6.36%)  11 3/173 (1.73%)  3
Pyrexia * 1  23/173 (13.29%)  25 18/173 (10.40%)  21
Investigations     
Platelet count decreased * 1  9/173 (5.20%)  9 6/173 (3.47%)  6
Metabolism and nutrition disorders     
Hyperglycaemia * 1  6/173 (3.47%)  7 9/173 (5.20%)  10
Hyperphosphataemia * 1  9/173 (5.20%)  9 4/173 (2.31%)  4
Nervous system disorders     
Headache * 1  13/173 (7.51%)  14 5/173 (2.89%)  5
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (Unspecified)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Dr. Angela Capriati, Corporate Clinical Research Director
Organization: Menarini Ricerche S.p.A.
Phone: +39 055 5680 ext 9933
Responsible Party: Menarini Group
ClinicalTrials.gov Identifier: NCT01724528     History of Changes
Other Study ID Numbers: FLO-01
2012-000776-42 ( EudraCT Number )
First Submitted: November 7, 2012
First Posted: November 9, 2012
Results First Submitted: October 27, 2014
Results First Posted: November 3, 2014
Last Update Posted: November 3, 2014