Tumor Lysis Syndrome
Conditions
Keywords
Febuxostat, Tumor lysis syndrome, leukemia, lymphoma
Brief summary
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
Detailed description
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.
Interventions
DRUGFebuxostat
Standard dose PO (per os) from Day 1 to Day 7 (can be continued up to DAY 9 at investigator's discretion)
DRUGAllopurinol
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)
Sponsors
Menarini Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients scheduled for first cytotoxic chemotherapy cycle, regardless of the line of treatment, because of hematologic malignancies at intermediate or high risk of TLS (according to the TLS risk stratification, Cairo M et al, British Journal of Haematology, 2010)candidate to Allopurinol treatment or have no access to Rasburicase * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3 * Life expectancy \> 1 month
Exclusion criteria
* Patients known to be hypersensitive to Febuxostat or Allopurinol or to any of the components of the formulations * Patients with sUA levels ≥ 10 mg/dL at randomization * Patients receiving Febuxostat, Allopurinol or any other urate lowering therapy (e.g. Rasburicase, probenecid) within 30 days prior to randomization * Patients with severe renal and/or hepatic insufficiency * Patients with diagnosis of LTLS or CTLS at randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum Uric Acid (sUA) Level Control | 8 days | Area under the curve of sUA from baseline (Day 1) to the evaluation visit (Day 8) |
| Preservation of Renal Function | 8 days | Change in serum creatinine level from baseline (Day 1) to the evaluation visit (Day 8) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Responder Rate | 6 days | 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 Laboratory Tumor Lysis Syndrome (LTLS) | 6 days | 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 Clinical Tumor Lysis Syndrome (CTLS) | 6 days | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Treatment Emergent Signs or Symptoms (TESS) | 14 ± 2 days | Incidence, severity, seriousness and treatment-causality of TESS |
Participant flow
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)
Participants by arm
| Arm | Count |
|---|---|
| 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) | 173 |
| 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) | 173 |
| Total | 346 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 0 |
| Overall Study | Patient refused to attend last visit | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Total | Allopurinol | Febuxostat |
|---|---|---|---|
| Age, Continuous | 58.4 years STANDARD_DEVIATION 13.75 | 58.3 years STANDARD_DEVIATION 13.26 | 58.5 years STANDARD_DEVIATION 14.26 |
| serum uric acid (sUA) > 7.5 mg/dL | 43 participants | 21 participants | 22 participants |
| serum uric acid (sUA) < or = 7.5 mg/dL | 303 participants | 152 participants | 151 participants |
| Sex: Female, Male Female | 132 Participants | 67 Participants | 65 Participants |
| Sex: Female, Male Male | 214 Participants | 106 Participants | 108 Participants |
| TLS risk High | 62 participants | 32 participants | 30 participants |
| TLS risk Intermediate | 284 participants | 141 participants | 143 participants |
| Type of Hematologic Malignancy Acute leukemia | 59 participants | 25 participants | 34 participants |
| Type of Hematologic Malignancy Chronic lymphocytic leukemia | 174 participants | 94 participants | 80 participants |
| Type of Hematologic Malignancy Lymphoma | 113 participants | 54 participants | 59 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 116 / 173 | 112 / 173 |
| serious Total, serious adverse events | 21 / 173 | 6 / 173 |
Outcome results
Primary
Preservation of Renal Function
Change in serum creatinine level from baseline (Day 1) to the evaluation visit (Day 8)
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Febuxostat | Preservation of Renal Function | -0.83 change % | Standard Deviation 26.977 |
| Allopurinol | Preservation of Renal Function | -4.92 change % | Standard Deviation 16.695 |
Comparison: 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 covariatesp-value: 0.090395% CI: [-0.6467, 8.8406]ANCOVA
Primary
Serum Uric Acid (sUA) Level Control
Area under the curve of sUA from baseline (Day 1) to the evaluation visit (Day 8)
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Febuxostat | Serum Uric Acid (sUA) Level Control | 514.0 mg x hour/dL | Standard Deviation 225.71 |
| Allopurinol | Serum Uric Acid (sUA) Level Control | 708.0 mg x hour/dL | Standard Deviation 234.42 |
Comparison: 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 covariatesp-value: <0.000195% CI: [-238.6, -154.988]ANCOVA
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
Time frame: 6 days
Population: ITT; no imputation applied
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat | Assessment of Clinical Tumor Lysis Syndrome (CTLS) | 1.7 % of patients with CTLS occurrence |
| Allopurinol | Assessment of Clinical Tumor Lysis Syndrome (CTLS) | 1.2 % of patients with CTLS occurrence |
p-value: 195% CI: [0.9691, 1.0199]Chi-squared
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.
Time frame: 6 days
Population: ITT; no imputation applied
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat | Assessment of Laboratory Tumor Lysis Syndrome (LTLS) | 8.1 % of patients with LTLS occurrence |
| Allopurinol | Assessment of Laboratory Tumor Lysis Syndrome (LTLS) | 9.2 % of patients with LTLS occurrence |
p-value: 0.848895% CI: [0.4408, 1.7369]Chi-squared
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
Time frame: 6 days
Population: Intention to Treat (ITT; no imputation applied
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat | Treatment Responder Rate | 1.7 % of patients who fail to respond |
| Allopurinol | Treatment Responder Rate | 4.0 % of patients who fail to respond |
p-value: 0.199395% CI: [-0.0153, 0.0654]Wilson's confidence interval
Other Pre-specified
Treatment Emergent Signs or Symptoms (TESS)
Incidence, severity, seriousness and treatment-causality of TESS
Time frame: 14 ± 2 days