Fluorouracil is recommended for the topical treatment of multiple actinic or solar keratoses. In the 5% strength, it is also useful in the treatment of superficial basal cell carcinomas when conventional methods are impractical, such as with multiple lesions or difficult treatment sites.
There is evidence that the metabolism of Fluorouracil in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid. In this manner, Fluorouracil interferes with the synthesis of deoxyribonucleic acid (DNA) and to a lesser extent inhibits the formation of ribonucleic acid (RNA). As DNA and RNA are essential for cell division and growth, the effect of Fluorouracil may be to create a thymine deficiency, which, provokes unbalanced growth and death of the cell. The effects of DNA and RNA deprivation are most marked on those cells that grow more rapidly and take up Fluorouracil at a more rapid rate. The catabolic metabolism of Fluorouracil results in degradation products (e.g., CO2, urea, α-fluoro-β-alanine), which are inactive. Systemic absorption studies of topically applied Fluorouracil have been performed on patients with actinic keratoses using tracer amounts of 14C-labeled Fluorouracil added to a 5% preparation. All patients had been receiving nonlabeled Fluorouracil until the peak of the inflammatory reaction occurred (2 to 3 weeks), ensuring that the time of maximum absorption was used for measurement. One gram of labeled preparation was applied to the entire face and neck and left in place for 12 hours. Urine samples were collected. At the end of 3 days, the total recovery ranged between 0.48% and 0.94%, with an average of 0.76%, indicating that approximately 5.98% of the topical dose was absorbed systemically. If applied twice daily, this would indicate systemic absorption of topical Fluorouracil to be in the range of 5 to 6 mg per daily dose of 100 mg. In an additional study, negligible amounts of labeled material were found in plasma, urine, and expired CO2 after 3 days of treatment with topically applied 14C-labeled Fluorouracil.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
458
Apply cream twice daily in an amount sufficient to cover the lesions. Fluorouracil should be applied preferably with a nonmetal applicator or suitable glove. If Fluorouracil is applied with the fingers, the hands should be washed immediately afterward.
Apply cream twice daily in an amount sufficient to cover the lesions. Fluorouracil should be applied preferably with a nonmetal applicator or suitable glove. If Fluorouracil is applied with the fingers, the hands should be washed immediately afterward.
CBCC Global Research Site 005
Bakersfield, California, United States
CBCC Global Research Site 006
Cerritos, California, United States
CBCC Global Research Site 004
Lauderdale Lakes, Florida, United States
CBCC Global Research Site 001
Miami, Florida, United States
Therapeutic equivalence with Reference product
Therapeutic equivalence will be evaluated for the primary endpoint at Visit 4 in the PP population. If the 90% confidence interval on the absolute difference between the proportion of subjects who are considered a complete cure in the Test and the Reference product groups (pT - pR) is contained within \[-20%, +20%\], then therapeutic equivalence of the Test product to the Reference product will be considered to have been demonstrated
Time frame: 6 weeks
Superiority to Placebo
The superiority of the Test and Reference products against the Placebo product will be evaluated for the primary endpoint at Visit 4 in the modified Intent-to-Treat (mITT) population using the last observation carried forward (LOCF). If the proportion of subjects who are considered a complete cure in the Test and the Reference product groups is numerically and statistically superior to that of the Placebo (p \< 0.05; using a two-sided Cochran-Mantel-Haenszel \[CMH\] test, stratified by clinical site), then the superiority of the Test and Reference products over Placebo will be concluded
Time frame: 6 weeks
Primary Efficacy End Point
The primary efficacy endpoint is the proportion of subjects in each treatment group with treatment success, defined as 100% clearance of all AK lesions (baseline or target AK lesions and any new AK lesions) within the designated treatment area (i.e., complete cure), assessed at study Week 6 (Day 43 ± 4, which is 4 weeks after completion of 2 weeks of treatment)
Time frame: 6 weeks
Safety Analysis
All Safety analysis will be based on the Safety population. Adverse events will be classified using standard MedDRA terminology Version 24.0 or higher and summarized by treatment group. Summary tables comparing the type, incidence, date of onset, date of resolution, severity, action taken, outcome, and Investigator's opinion of relationship to the study product will be prepared by treatment group. If sufficient data exist, AE frequencies will be compared between treatments using Fisher's exact test. If the global Fisher's exact test is statistically significant among the three treatment groups at the 5% alpha level (i.e., p \< 0.05), then Fisher's exact test using only the Test and Reference groups may be performed to identify any potential statistically significant differences that are clinically relevant between the two active treatment groups
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Apply cream twice daily in an amount sufficient to cover the lesions. Fluorouracil should be applied preferably with a nonmetal applicator or suitable glove. If Fluorouracil is applied with the fingers, the hands should be washed immediately afterward.
CBCC Global Research Site 002
Miami, Florida, United States
CBCC Global Research Site 003
Miramar, Florida, United States
CBCC Global Research Site 007
Sugarloaf, Pennsylvania, United States
Time frame: 6 weeks