LEVULAN KERASTICK for topical solution plus blue light at 6-10.9 J/cm 2, has been used to treat actinic keratoses of the face or scalp in 342 subjects in seven clinical trials. Phase 3 trials ALA-018 and ALA-019 were two, identically designed, multicenter, two-arm trials using LEVULAN KERASTICK topical solution plus illumination from the BLU-U Blue Light Photodynamic Therapy Illuminator for 1000 seconds (16 minutes and 40 seconds) for a nominal exposure of 10 J/cm 2. Subjects were excluded from these trials who had a history of cutaneous photosensitization, porphyria, hypersensitivity to porphyrins, photodermatosis, or inherited or acquired coagulation defects. A minimum of 4 and a maximum of 15 clinically typical, discrete, Grade 1 (slightly palpable actinic keratoses: better felt than seen), or Grade 2 (moderately thick actinic keratoses: easily seen and felt) target actinic keratoses were identified (see Table 5for definitions). Target lesions on the face or on the scalp, but not on both locations in the same subject, received treatment. The subjects were randomized to receive treatment either with the LEVULAN KERASTICK topical solution plus BLU-U Blue Light Photodynamic Therapy Illuminator or vehicle plus BLU-U Blue Light Photodynamic Therapy Illuminator. Subjects were randomized at a 3 to 1 LEVULAN KERASTICK topical solution to vehicle ratio. A total of 243 subjects were enrolled in two Phase 3 trials (ALA-018, ALA-019). Lesions were designated as cleared (complete response) if the lesion had completely cleared and adherent scaling plaques of actinic keratoses were no longer evident on the surface of the treated skin when palpated. The percentage of subjects in whom 75% or more of treated lesions were cleared, and the percentage of subjects in whom 100% of treated lesions were cleared (Complete Responders), for each trial 8 weeks after treatment are shown in Table 4. 

Because ALA-018 and ALA-019 had identical protocols, the combined results from the two trials are shown in the following tables. For actinic keratoses with a variety of thicknesses (excluding very thick, Grade 3 actinic keratoses which were not studied in the Phase 3 trials), LEVULAN KERASTICK topical solution plus BLU-U Blue Light Photodynamic Therapy Illuminator is more effective than vehicle plus BLU-U Blue Light Photodynamic Therapy Illuminator, but as shown in Table 5, the percentage of lesions with complete responses at 8 weeks after treatment with LEVULAN KERASTICK topical solution plus blue light illumination was lower for those lesions that were thicker at baseline. Efficacy of LEVULAN KERASTICK topical solution plus BLU-U Blue Light Photodynamic Therapy Illuminator on higher grade lesions was not studied in the Phase 3 clinical efficacy trials. 

Those subjects who were not Complete Responders at Week 8 had retreatment of the persistent target lesions at Week 8. Among the subjects undergoing retreatment, efficacy results seen at 12 weeks after the initial treatment, i.e., at 4 weeks after the second treatment, are shown in Table 6. 

The efficacy results seen at 12 weeks after treatment, which include the results at 12 weeks for those subjects who received a single treatment as well as the results at 12 weeks for those subjects who received a second treatment at week 8, are shown in Table 7. 

Among Complete Responders at Week 8, 93% (in ALA-018) and 83% (in ALA-019) maintained complete response at Week 12. Among subjects with scalp lesions, the percentage of subjects with 100% of actinic keratosis lesions having complete response declined from Week 8 (55%) to Week 12 (50%), because there were more subjects with scalp lesions with 100% of actinic keratosis lesions cleared at Week 8 who had a recurrence of a lesion by Week 12 than there were subjects with scalp lesions who had retreatment of persistent lesions at Week 8 and who then achieved 100% of actinic keratosis lesions cleared by Week 12. Subjects did not receive follow-up past 12 weeks after the initial treatment.

Subject outcomes recorded in the two Phase 3 trials are depicted in the following flowchart, in which Complete Responders are designated clear. Seven subjects in the active treatment arm and three subjects in the vehicle treatment arm withdrew or were lost to follow-up. Three subjects in the active treatment arm were treated at baseline but did not return for evaluation until Week 12. One subject in the active treatment arm and two in the vehicle treatment arm who were not clear at Week 8 did not receive retreatment.

An open-label trial enrolled 110 subjects with 4 to 10 clinically typical, discrete actinic keratoses on the face or scalp, but not both locations. The target lesions were treated with the LEVULAN KERASTICK topical solution plus BLU-U Blue Light Photodynamic Therapy Illuminator. Any treated lesions that were not clear at Month 2 (Week 8) were re-treated. Subjects were followed monthly for 12 months. Lesions were designated as cleared if the lesion had completely cleared and adherent scaling plaques of actinic keratoses were no longer evident on the surface of the treated skin when palpated. The percentages of subjects in whom 100% of treated lesions were cleared (Complete Responders) by month, starting at Month 3 (Week 12), are shown in Figure 4. Of the 72 subjects with 100% of treated lesions cleared (Complete Responders) at Month 3, 53% had a recurrence by Month 12. A total of 748 individual lesions were treated; 539 were treated once and 209 were treated twice. At Month 3, 624 lesions (83%) were cleared. From Month 3 through Month 12 of the trial, 476 lesions (64%) remained clear. See Figure 5. Of the 624 treated lesions determined cleared at Month 3, 24% had recurred by Month 12, while 5% were lost to follow-up and their recurrence status is unknown.