Trial Outcomes & Findings for Safety and Efficacy Study for the Field-directed Treatment of Actinic Keratosis (AK) With Photodynamic Therapy (PDT) (NCT NCT01966120)

NCT ID: NCT01966120

Last Updated: 2023-07-28

Results Overview

All efficacy variables were evaluated for the FAS. The primary efficacy variable was also analyzed for the PP population. All subgroup analyses were carried out for the FAS. Data for size and grade of AK lesions were analyzed using the last observation carried forward (LOCF) approach, affecting the response rates evaluation. Due to the small amount of missing data in the study, which did not have any relevant impact on primary results, sensitivity analyses for missing data were not performed. The primary efficacy variable was the overall patient complete response 12 weeks after the last PDT. An overall complete responder was defined as a patient in whom all treated actinic keratosis (AK) lesions were cleared (Olsen score of 0) after the last PDT, i.e. after PDT 1 or after PDT 2 if re-treatment was performed.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

87 participants

Primary outcome timeframe

12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT

Results posted on

2023-07-28

Participant Flow

Trial was conducted in Germany with 7 study sites (Bonn, Dresden, Munich, Wuppertal, Mönchengladbach, Cologne, and Recklinghausen) who recruited patients.

94 patients were screened, 87 patients were randomized (55 patients to BF-200 ALA and 32 patients to placebo) and treated. 7 patients were screening failures: 3 withdrew consent, 2 did not meet the in- /exclusion criteria, and 2 failed for other reasons (recruitment stop).

Participant milestones

Participant milestones
Measure	BF-200 ALA Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the investigational medicinal product (IMP) was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Overall Study STARTED	55	32
Overall Study COMPLETED	54	26
Overall Study NOT COMPLETED	1	6

Reasons for withdrawal

Reasons for withdrawal
Measure	BF-200 ALA Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the investigational medicinal product (IMP) was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Overall Study Withdrawal by Subject	0	5
Overall Study Lost to Follow-up	1	1

Baseline Characteristics

Safety and Efficacy Study for the Field-directed Treatment of Actinic Keratosis (AK) With Photodynamic Therapy (PDT)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	BF-200 ALA n=55 Participants Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=32 Participants Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Total n=87 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	9 Participants n=5 Participants	4 Participants n=7 Participants	13 Participants n=5 Participants
Age, Categorical >=65 years	46 Participants n=5 Participants	28 Participants n=7 Participants	74 Participants n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	3 Participants n=7 Participants	8 Participants n=5 Participants
Sex: Female, Male Male	50 Participants n=5 Participants	29 Participants n=7 Participants	79 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	55 Participants n=5 Participants	32 Participants n=7 Participants	87 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	55 Participants n=5 Participants	32 Participants n=7 Participants	87 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Germany	55 participants n=5 Participants	32 participants n=7 Participants	87 participants n=5 Participants

PRIMARY outcome

Timeframe: 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT

Population: Full Analysis Set (FAS)

Outcome measures

Outcome measures
Measure	BF-200 ALA n=55 Participants Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=32 Participants Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Overall Patient Complete Response 12 Weeks After the Last Photodynamic Therapy (PDT)	90.9 percentage of participants Interval 80.0 to 97.0	21.9 percentage of participants Interval 9.3 to 40.0

PRIMARY outcome

Timeframe: 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT

Population: Per Protocol Set (PP)

All efficacy variables were evaluated for the FAS. The primary efficacy variable was also analyzed for the PP population. All subgroup analyses were carried out for the FAS. Data for size and grade of AK lesions were analyzed using the last observation carried forward (LOCF) approach, affecting the response rates evaluation. Due to the small amount of missing data in the study, which did not have any relevant impact on primary results, sensitivity analyses for missing data were not performed. The primary efficacy variable was the overall patient complete response 12 weeks after the last PDT. An overall complete responder was defined as a patient in whom all treated AK lesions were cleared (Olsen score of 0) after the last PDT, i.e. after PDT 1 or after PDT 2 if re-treatment was performed.

Outcome measures

Outcome measures
Measure	BF-200 ALA n=50 Participants Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=27 Participants Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Overall Patient Complete Response 12 Weeks After the Last PDT (PP)	90.0 percentage of participants Interval 78.2 to 96.7	25.9 percentage of participants Interval 11.1 to 46.3

SECONDARY outcome

Timeframe: 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT

Population: Full Analysis Set (FAS) 6 patients (1 BF-200 ALA and 5 Placebo patients) had a missing evaluation of the second biopsy 12 weeks after PDT.

For the secondary confirmatory analysis, several superiority hypotheses were tested within a pre-defined hierarchic multiple testing procedure as described in the Statistical Analysis Protocoll (SAP). The key secondary efficacy variables were tested strictly in a pre-defined order to ensure the family-wise error rate (FWER) and the testing procedure had to be stopped once the first non-significant test was obtained. The results of the confirmatory analysis are presented in the order pre-defined by the confirmatory testing procedure. Assessments of the patient histopathological confirmed response (HCR) rates were based on the results from the biopsy taken 12 weeks after the last PDT from a representative AK lesion selected at screening. If the biopsy result for a patient revealed a residual AK, the patient was considered "not cleared" for the analysis irrespectively of the investigator's clinical assessment.

Outcome measures

Outcome measures
Measure	BF-200 ALA n=54 Participants Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=27 Participants Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Patient Histopathological Confirmed Response Rate	77.8 percentage of participants Interval 64.4 to 88.0	22.2 percentage of participants Interval 8.6 to 42.3

SECONDARY outcome

Timeframe: 12 weeks after PDT 1

Population: Full Analysis Set (FAS)

The second key secondary efficacy variable in the hierarchic test procedure was the patient complete response (complete clearance of all treated AK lesions) assessed at 12 weeks after PDT 1.

Outcome measures

Outcome measures
Measure	BF-200 ALA n=55 Participants Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=32 Participants Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Patient Complete Response 12 Weeks After PDT 1	61.8 percentage of participants Interval 47.7 to 74.6	9.4 percentage of participants Interval 2.0 to 25.0

SECONDARY outcome

Timeframe: 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT

Population: Full Analysis Set (FAS)

The third key secondary efficacy variable in the hierarchic test procedure was the lesion complete response (completely cleared individual AK lesions) assessed at 12 weeks after last PDT.

Outcome measures

Outcome measures
Measure	BF-200 ALA n=298 Number of Lesions Analyzed Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=173 Number of Lesions Analyzed Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Lesion Complete Response 12 Weeks After Last PDT	94.3 percentage of lesions Interval 91.0 to 96.6	32.9 percentage of lesions Interval 26.0 to 40.5

SECONDARY outcome

Timeframe: 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT

Population: Full Analysis Set (FAS)

The fourth key secondary efficacy variable in the hierarchic test procedure was the patient partial response (defined as complete clearance of at least 75% of treated AK lesions) assessed at 12 weeks after last PDT.

Outcome measures

Outcome measures
Measure	BF-200 ALA n=55 Participants Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=32 Participants Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Patient Partial Response 12 Weeks After Last PDT	94.5 percentage of participants Interval 84.9 to 98.9	25 percentage of participants Interval 11.5 to 43.4

SECONDARY outcome

Timeframe: 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT

Population: Full Analysis Set (FAS)

The fifth key secondary efficacy variable in the hierarchic test procedure was the change from baseline in the total lesion area per patient assessed at 12 weeks after last PDT.

Outcome measures

Outcome measures
Measure	BF-200 ALA n=55 Participants Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=32 Participants Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Change of Total Lesion Area 12 Weeks After Last PDT	-98.2 percentage of lesion area change Standard Deviation 9.65	-45.5 percentage of lesion area change Standard Deviation 42.96

SECONDARY outcome

Timeframe: 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT

Population: Full Analysis Set (FAS)

Study personnel assessed and recorded the skin quality of the treated field(s) at baseline and at the end-of-study visit including skin surface, hyperpigmentation, hypopigmentation, mottled or irregular pigmentation, degree of scarring and atrophy. Upon visual examination of the treated field(s), the investigator coded the intensity of each skin parameter on a scale of 0 to 3, where 0 = none, 1 = mild, 2 = moderate, and 3 = severe. The cosmetic outcome evaluations were based on the sum score of the skin quality assessment (sum of all ratings for each skin parameter) at the end-of-study visit (Visit 4 or Visit 6, if retreated). The outcome was calculated using a 5-point scale ranging from "very good" (0) to "impaired" (4) based on the change of the skin quality assessments compared to baseline (0 = 2 points improvement; 1 = 1 point improvement; 2 = no change; 3 = 1 point worsened; 4 = at least 2 points worsened).

Outcome measures

Outcome measures
Measure	BF-200 ALA n=54 Participants Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=29 Participants Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Overall Cosmetic Outcome 12 Weeks After Last PDT for Patients With Sum Score at Baseline of 0 to 3 Very good	35.2 percentage of participants Interval 22.7 to 49.4	17.2 percentage of participants Interval 5.8 to 35.8
Overall Cosmetic Outcome 12 Weeks After Last PDT for Patients With Sum Score at Baseline of 0 to 3 Good	24.1 percentage of participants Interval 13.5 to 37.6	13.8 percentage of participants Interval 3.9 to 31.7
Overall Cosmetic Outcome 12 Weeks After Last PDT for Patients With Sum Score at Baseline of 0 to 3 Satisfactory	24.1 percentage of participants Interval 13.5 to 37.6	20.7 percentage of participants Interval 8.0 to 39.7
Overall Cosmetic Outcome 12 Weeks After Last PDT for Patients With Sum Score at Baseline of 0 to 3 Unsatisfactory	11.1 percentage of participants Interval 4.2 to 22.6	27.6 percentage of participants Interval 12.7 to 47.2
Overall Cosmetic Outcome 12 Weeks After Last PDT for Patients With Sum Score at Baseline of 0 to 3 Impaired	5.6 percentage of participants Interval 1.2 to 15.4	20.7 percentage of participants Interval 8.0 to 39.7

SECONDARY outcome

Timeframe: 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT

Population: Full Analysis Set (FAS)

Outcome measures

Outcome measures
Measure	BF-200 ALA n=48 Participants Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=26 Participants Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Overall Cosmetic Outcome 12 Weeks After Last PDT for Patients With Sum Score at Baseline of 1 to 3 Very good	39.6 percentage of participants Interval 25.8 to 54.7	19.2 percentage of participants Interval 6.6 to 39.4
Overall Cosmetic Outcome 12 Weeks After Last PDT for Patients With Sum Score at Baseline of 1 to 3 Good	27.1 percentage of participants Interval 15.3 to 41.8	15.4 percentage of participants Interval 4.4 to 34.9
Overall Cosmetic Outcome 12 Weeks After Last PDT for Patients With Sum Score at Baseline of 1 to 3 Satisfactory	22.9 percentage of participants Interval 12.0 to 37.3	23.1 percentage of participants Interval 9.0 to 43.6
Overall Cosmetic Outcome 12 Weeks After Last PDT for Patients With Sum Score at Baseline of 1 to 3 Unsatisfactory	6.3 percentage of participants Interval 1.3 to 17.2	26.9 percentage of participants Interval 11.6 to 47.8
Overall Cosmetic Outcome 12 Weeks After Last PDT for Patients With Sum Score at Baseline of 1 to 3 Impaired	4.2 percentage of participants Interval 0.5 to 14.3	15.4 percentage of participants Interval 4.4 to 34.9

OTHER_PRE_SPECIFIED outcome

Timeframe: 12 months after last treatment (PDT-1 or PDT-2, if re-treated)

Population: Full analysis set in follow-up phase (FAS-FUP). Recurrence rate was only analyzed in patients with complete clearance/response 12 weeks after the last treatment (PDT-1 or PDT-2, if re-treated). Complete response was achieved if all treated lesions of the patient were cleared 12 weeks after the last treatment (PDT-1 or PDT-2, if re-treated).

Cumulative numbers of patients with complete response who showed recurrences 12 months after last treatment (PDT-1 or PDT-2, if re-treated). A patient with complete response was regarded as recurrent if at least one baseline AK lesion recurred during the follow-up (FU). Complete response was achieved if all treated lesions of the patient were cleared 12 weeks after the last treatment (PDT-1 or PDT-2, if re-treated). Lesions that showed recurrence at 6-months (FU1) were also defined as recurrent at 12-months follow-up (FU2).

Outcome measures

Outcome measures
Measure	BF-200 ALA n=49 Participants Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=7 Participants Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Patient Recurrence Rate in Follow-up (Cumulative) Patients cleared 12 weeks after last PDT with any recurrent baseline AK lesion at 12-months FU	18 Participants	1 Participants
Patient Recurrence Rate in Follow-up (Cumulative) Patients cleared 12 weeks after last PDT still completely cleared at 12 months FU	31 Participants	6 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 12 months after last treatment (PDT-1 or PDT-2, if retreated)

Population: Full analysis set in follow-up phase (FAS-FUP). Lesion recurrence rate was only analyzed in lesions which were cleared 12 weeks after the last treatment (PDT-1 or PDT-2, if re-treated).

Cumulative recurrence rate in follow-up of baseline AK lesions that were cleared 12 weeks after the last treatment (PDT-1 or PDT-2, if re-treated) and recurred during 12 months follow-up. Lesions that showed recurrence at 6-months (FU1) were also defined as recurrent at 12-months follow-up (FU2).

Outcome measures

Outcome measures
Measure	BF-200 ALA n=276 AK Lesions Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=52 AK Lesions Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Lesion Recurrence Rate in Follow-up (Cumulative) Baseline AK lesions cleared 12 weeks after last PDT with recurrence during 12 months FU	25 AK lesions	1 AK lesions
Lesion Recurrence Rate in Follow-up (Cumulative) Baseline AK lesions cleared 12 weeks after last PDT and are still completely cleared at 12 months FU	251 AK lesions	51 AK lesions

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months after last treatment (PDT-1 or PDT-2, if re-treated)

Population: Full analysis set in follow-up (FAS-FUP), considering only patients with data at 6-months follow-up.

Frequency of skin quality changes in follow-up compared to baseline. Study personnel assessed and recorded the skin quality of the treated field(s) at baseline and at the follow up visit (6 months) including skin surface, hyperpigmentation, hypopigmentation, mottled or irregular pigmentation, degree of scarring and atrophy. Upon visual examination of the treated field(s), the investigator coded the intensity of each skin parameter on a scale of 0 to 3, where 0 = none, 1 = mild, 2 = moderate, and 3 = severe.

Outcome measures

Outcome measures
Measure	BF-200 ALA n=54 Participants Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=27 Participants Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Skin Quality in Follow-up (6 Months) Skin surface (roughness/dryness/scaliness) · None	34 Participants	15 Participants
Skin Quality in Follow-up (6 Months) Skin surface (roughness/dryness/scaliness) · Mild	15 Participants	9 Participants
Skin Quality in Follow-up (6 Months) Skin surface (roughness/dryness/scaliness) · Moderate	4 Participants	3 Participants
Skin Quality in Follow-up (6 Months) Skin surface (roughness/dryness/scaliness) · Severe	1 Participants	0 Participants
Skin Quality in Follow-up (6 Months) Hyperpigmentation (independent of texture change or hypopigmentation) · None	35 Participants	13 Participants
Skin Quality in Follow-up (6 Months) Hyperpigmentation (independent of texture change or hypopigmentation) · Mild	16 Participants	10 Participants
Skin Quality in Follow-up (6 Months) Hyperpigmentation (independent of texture change or hypopigmentation) · Moderate	3 Participants	4 Participants
Skin Quality in Follow-up (6 Months) Hyperpigmentation (independent of texture change or hypopigmentation) · Severe	0 Participants	0 Participants
Skin Quality in Follow-up (6 Months) Hypopigmentation (independent of texture change or hyperpigmentation) · None	42 Participants	15 Participants
Skin Quality in Follow-up (6 Months) Hypopigmentation (independent of texture change or hyperpigmentation) · Mild	10 Participants	9 Participants
Skin Quality in Follow-up (6 Months) Hypopigmentation (independent of texture change or hyperpigmentation) · Moderate	2 Participants	3 Participants
Skin Quality in Follow-up (6 Months) Hypopigmentation (independent of texture change or hyperpigmentation) · Severe	0 Participants	0 Participants
Skin Quality in Follow-up (6 Months) Mottled or irregular pigmentation (both hyper- and hypopigmentation · None	37 Participants	14 Participants
Skin Quality in Follow-up (6 Months) Mottled or irregular pigmentation (both hyper- and hypopigmentation · Mild	13 Participants	9 Participants
Skin Quality in Follow-up (6 Months) Mottled or irregular pigmentation (both hyper- and hypopigmentation · Moderate	4 Participants	4 Participants
Skin Quality in Follow-up (6 Months) Mottled or irregular pigmentation (both hyper- and hypopigmentation · Severe	0 Participants	0 Participants
Skin Quality in Follow-up (6 Months) Degree of scarring (independent of pigmentary changes) · None	44 Participants	20 Participants
Skin Quality in Follow-up (6 Months) Degree of scarring (independent of pigmentary changes) · Mild	8 Participants	5 Participants
Skin Quality in Follow-up (6 Months) Degree of scarring (independent of pigmentary changes) · Moderate	2 Participants	2 Participants
Skin Quality in Follow-up (6 Months) Degree of scarring (independent of pigmentary changes) · Severe	0 Participants	0 Participants
Skin Quality in Follow-up (6 Months) Atrophy · None	48 Participants	21 Participants
Skin Quality in Follow-up (6 Months) Atrophy · Mild	4 Participants	4 Participants
Skin Quality in Follow-up (6 Months) Atrophy · Moderate	2 Participants	2 Participants
Skin Quality in Follow-up (6 Months) Atrophy · Severe	0 Participants	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 12 months after last treatment (PDT-1 or PDT-2, if re-treated)

Population: Full analysis set in follow-up (FAS-FUP), considering only patients with data at 12-months follow-up.

Frequency of skin quality changes in follow-up compared to baseline. Study personnel assessed and recorded the skin quality of the treated field(s) at baseline and at the follow up visit (12 months) including skin surface, hyperpigmentation, hypopigmentation, mottled or irregular pigmentation, degree of scarring and atrophy. Upon visual examination of the treated field(s), the investigator coded the intensity of each skin parameter on a scale of 0 to 3, where 0 = none, 1 = mild, 2 = moderate, and 3 = severe.

Outcome measures

Outcome measures
Measure	BF-200 ALA n=54 Participants Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=26 Participants Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Skin Quality in Follow-up (12 Months) Skin surface (roughness/dryness/scaliness) · None	39 Participants	15 Participants
Skin Quality in Follow-up (12 Months) Skin surface (roughness/dryness/scaliness) · Mild	14 Participants	9 Participants
Skin Quality in Follow-up (12 Months) Skin surface (roughness/dryness/scaliness) · Moderate	1 Participants	2 Participants
Skin Quality in Follow-up (12 Months) Skin surface (roughness/dryness/scaliness) · Severe	0 Participants	0 Participants
Skin Quality in Follow-up (12 Months) Hyperpigmentation (independent of texture change or hypopigmentation) · None	41 Participants	16 Participants
Skin Quality in Follow-up (12 Months) Hyperpigmentation (independent of texture change or hypopigmentation) · Mild	13 Participants	9 Participants
Skin Quality in Follow-up (12 Months) Hyperpigmentation (independent of texture change or hypopigmentation) · Moderate	0 Participants	1 Participants
Skin Quality in Follow-up (12 Months) Hyperpigmentation (independent of texture change or hypopigmentation) · Severe	0 Participants	0 Participants
Skin Quality in Follow-up (12 Months) Hypopigmentation (independent of texture change or hyperpigmentation) · None	48 Participants	18 Participants
Skin Quality in Follow-up (12 Months) Hypopigmentation (independent of texture change or hyperpigmentation) · Mild	6 Participants	7 Participants
Skin Quality in Follow-up (12 Months) Hypopigmentation (independent of texture change or hyperpigmentation) · Moderate	0 Participants	1 Participants
Skin Quality in Follow-up (12 Months) Hypopigmentation (independent of texture change or hyperpigmentation) · Severe	0 Participants	0 Participants
Skin Quality in Follow-up (12 Months) Mottled or irregular pigmentation (both hyper- and hypopigmentation · None	44 Participants	19 Participants
Skin Quality in Follow-up (12 Months) Mottled or irregular pigmentation (both hyper- and hypopigmentation · Mild	9 Participants	4 Participants
Skin Quality in Follow-up (12 Months) Mottled or irregular pigmentation (both hyper- and hypopigmentation · Moderate	1 Participants	3 Participants
Skin Quality in Follow-up (12 Months) Mottled or irregular pigmentation (both hyper- and hypopigmentation · Severe	0 Participants	0 Participants
Skin Quality in Follow-up (12 Months) Degree of scarring (independent of pigmentary changes) · None	50 Participants	23 Participants
Skin Quality in Follow-up (12 Months) Degree of scarring (independent of pigmentary changes) · Mild	4 Participants	3 Participants
Skin Quality in Follow-up (12 Months) Degree of scarring (independent of pigmentary changes) · Moderate	0 Participants	0 Participants
Skin Quality in Follow-up (12 Months) Degree of scarring (independent of pigmentary changes) · Severe	0 Participants	0 Participants
Skin Quality in Follow-up (12 Months) Atrophy · None	52 Participants	24 Participants
Skin Quality in Follow-up (12 Months) Atrophy · Mild	2 Participants	2 Participants
Skin Quality in Follow-up (12 Months) Atrophy · Moderate	0 Participants	0 Participants
Skin Quality in Follow-up (12 Months) Atrophy · Severe	0 Participants	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months after last treatment (PDT-1 or PDT-2, if re-treated)

Population: Full analysis set in follow-up (FAS-FUP), considering only patients with data at 6-months follow-up.

Patients' satisfaction of the overall cosmetic outcome was assessed at 6-months follow-up visit using a 5-point scale, where 0=very good, 1=good, 2=satisfactory, 3=unsatisfactory, and 4=impaired. The lowest rating is the best outcome, the highest rating is the worst outcome.

Outcome measures

Outcome measures
Measure	BF-200 ALA n=54 Participants Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=27 Participants Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Patients' Satisfaction in Follow-up (6 Months) Very good or good	79.6 percentage of patients Interval 66.5 to 89.4	59.3 percentage of patients Interval 38.8 to 77.6
Patients' Satisfaction in Follow-up (6 Months) Very good	27.8 percentage of patients Interval 16.5 to 41.6	33.3 percentage of patients Interval 16.5 to 54.0
Patients' Satisfaction in Follow-up (6 Months) Good	51.9 percentage of patients Interval 37.8 to 65.7	25.9 percentage of patients Interval 11.1 to 46.3
Patients' Satisfaction in Follow-up (6 Months) Satisfactory	16.7 percentage of patients Interval 7.9 to 29.3	25.9 percentage of patients Interval 11.1 to 46.3
Patients' Satisfaction in Follow-up (6 Months) Unsatisfactory	3.7 percentage of patients Interval 0.5 to 12.7	11.1 percentage of patients Interval 2.4 to 29.2
Patients' Satisfaction in Follow-up (6 Months) Impaired	0.0 percentage of patients Interval 0.0 to 6.6	3.7 percentage of patients Interval 0.1 to 19.0

OTHER_PRE_SPECIFIED outcome

Timeframe: 12 months after last treatment (PDT-1 or PDT-2, if re-treated)

Population: Full analysis set in follow-up (FAS-FUP), considering only patients with data at 12-months follow-up.

Patients' satisfaction of the overall cosmetic outcome was assessed at 12-months follow-up visit using a 5-point scale, where 0=very good, 1=good, 2=satisfactory, 3=unsatisfactory, and 4=impaired. The lowest rating is the best outcome, the highest rating is the worst outcome.

Outcome measures

Outcome measures
Measure	BF-200 ALA n=54 Participants Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=26 Participants Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Patients' Satisfaction in Follow-up (12 Months) Very good or good	77.8 percentage of patients Interval 64.4 to 88.0	69.2 percentage of patients Interval 48.2 to 85.7
Patients' Satisfaction in Follow-up (12 Months) Very good	35.2 percentage of patients Interval 22.7 to 49.4	26.9 percentage of patients Interval 11.6 to 47.8
Patients' Satisfaction in Follow-up (12 Months) Good	42.6 percentage of patients Interval 29.2 to 56.8	42.3 percentage of patients Interval 23.4 to 63.1
Patients' Satisfaction in Follow-up (12 Months) Satisfactory	18.5 percentage of patients Interval 9.3 to 31.4	26.9 percentage of patients Interval 11.6 to 47.8
Patients' Satisfaction in Follow-up (12 Months) Unsatisfactory	3.7 percentage of patients Interval 0.5 to 12.7	3.8 percentage of patients Interval 0.1 to 19.6
Patients' Satisfaction in Follow-up (12 Months) Impaired	0.0 percentage of patients Interval 0.0 to 6.6	0.0 percentage of patients Interval 0.0 to 13.2

Adverse Events

BF-200 ALA

Serious events: 2 serious events

Other events: 55 other events

Deaths: 0 deaths

Placebo to BF-200 ALA

Serious events: 0 serious events

Other events: 22 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	BF-200 ALA n=55 participants at risk Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=32 participants at risk Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
Injury, poisoning and procedural complications Femoral neck fracture	1.8% 1/55 • Number of events 1 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.	0.00% 0/32 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.
Cardiac disorders Acute myocardial infarction	1.8% 1/55 • Number of events 1 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.	0.00% 0/32 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.
Nervous system disorders Cerebrovascular accident	1.8% 1/55 • Number of events 1 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.	0.00% 0/32 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.
Musculoskeletal and connective tissue disorders Bursitis	1.8% 1/55 • Number of events 1 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.	0.00% 0/32 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.

Other adverse events

Other adverse events
Measure	BF-200 ALA n=55 participants at risk Photodynamic therapy with BF-200 ALA After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.	Placebo to BF-200 ALA n=32 participants at risk Photodynamic therapy with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before occlusion. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). This treatment was performed once and repeated after 12 weeks if no complete response was observed.
General disorders Application site pain	96.4% 53/55 • Number of events 162 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.	50.0% 16/32 • Number of events 30 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.
General disorders Application site erythema	92.7% 51/55 • Number of events 76 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.	34.4% 11/32 • Number of events 14 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.
General disorders Application site pruritus	38.2% 21/55 • Number of events 25 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.	28.1% 9/32 • Number of events 10 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.
General disorders Application site scab	36.4% 20/55 • Number of events 26 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.	3.1% 1/32 • Number of events 1 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.
General disorders Application site exfoliation	30.9% 17/55 • Number of events 21 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.	3.1% 1/32 • Number of events 1 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.
General disorders Application site oedema	21.8% 12/55 • Number of events 14 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.	3.1% 1/32 • Number of events 1 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.
General disorders Application site vesicles	10.9% 6/55 • Number of events 6 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.	0.00% 0/32 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.
General disorders Application site discomfort	9.1% 5/55 • Number of events 7 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.	0.00% 0/32 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.
General disorders Application site discharge	5.5% 3/55 • Number of events 5 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.	0.00% 0/32 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.
Infections and infestations Nasopharyngitis	10.9% 6/55 • Number of events 7 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.	0.00% 0/32 • up to 11 months Adverse Events (AEs) expected to occur as local discomfort were reported via patient questionnaires, local skin reactions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.

Additional Information

Clinical Trial Department,

Biofrontera Bioscience GmbH

Phone: +49 2148763226

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The only disclosure restriction on the PI is that the sponsor will review results communications prior to public release and has to approve in order to ensure the adequate reporting of study results. The sponsor can't refuse publication for unfair reasons.
Publication restrictions are in place

Restriction type: OTHER