Study to Evaluate the Safety of BF-200 ALA (Ameluz®) for... | NCT04319159

Label	Type	Description	Intervention Names
BF-200 ALA	Experimental	Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid). One single Photodynamic therapy (PDT).	Combination Product: BF-200 ALA and red light LED lamp

Name	Type	Description	Arm Group Labels	Other Names
BF-200 ALA and red light LED lamp	Combination Product	Combination Product: Photodynamic therapy (PDT) using BF-RhodoLED® (ALA-PDT, Ameluz®-PDT).	BF-200 ALA

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Assessment of Baseline-adjusted Plasma Concentration-time Curves for ALA After a Single PDT Treatment Applying 3 Tubes of BF-200 ALA in Conjunction With the BF-RhodoLED® Under Maximal Use Conditions in Subjects With Mild to Severe Actinic Keratosis.	Blood samples for ALA analysis for each subject were collected, starting at Visit 1 and then 0.5h prior to BF-200 ALA application for up to 10h afterwards. The concentrations of ALA in plasma were measured by an analytical laboratory using validated, internally standardized liquid chromatography-tandem mass spectrometry methods.	On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 hours post-dose (prior to illumination)
Assessment of Baseline-adjusted Plasma Concentration-time Curves for PpIX After a Single PDT Treatment Applying 3 Tubes of BF-200 ALA in Conjunction With the BF-RhodoLED® Under Maximal Use Conditions in Subjects With Mild to Severe Actinic Keratosis.	Blood samples for PpIX analysis for each subject were collected, starting at Visit 1 and then 0.5h prior to BF-200 ALA application for up to 10h afterwards. The concentrations of PpIX in plasma were measured by an analytical laboratory using validated, internally standardized liquid chromatography-tandem mass spectrometry methods.	On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 hours post-dose (prior to illumination)

Secondary Outcomes

Measure	Description	Time Frame
Evaluation of Baseline-adjusted Pharmacokinetic Parameters of ALA.	Parameter: AUC(0-t) (Area Under Curve); area under the baseline-adjusted plasma concentration-time curve from time zero to the last sampling time point at which the concentration was at or above lower limit of quantification; t(last) is defined as the last value >0 after baseline adjustment.	On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 hours post-dose (prior to illumination)

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Subjects with at least 12 distinctive and clinically confirmed mild to severe AK lesions (according to Olsen et al. 1991 (37)) with a diameter of ≥ 4 mm each, on either the face/scalp (including forehead, excluding eyes, nostrils, ears, and mouth) or the neck/trunk/extremities, within treatment field(s) of about 60 cm² in total. Treatment field(s) may be discontinuous but must be within 2 illumination areas of the BF-RhodoLED® lamp (6 cm x 16 cm each).
All genders 18-85 years of age (inclusive).
Willingness and ability of the subject to provide informed consent and to sign the Health Insurance Portability and Accountability Act (HIPAA) form. A study-specific informed consent form and HIPAA form must be obtained in writing for all subjects prior to starting any study procedures.
Willingness and ability to comply with study procedures, particularly willingness to receive one PDT with up to two illumination devices simultaneously.
Subjects with good general health and subjects with clinically stable medical conditions will be permitted to be included in the study.
Subjects receiving any drugs affecting coagulation (e.g. anticoagulants, anti-platelet drugs) should be on a stable dose.
Acceptance to abstain from extensive sunbathing and the use of solarium during the clinical study.
Women of child-bearing potential must have a negative serum pregnancy test and must use an adequate and highly effective or two effective methods of contraception throughout the study.

Exclusion Criteria:

Any known history of hypersensitivity to ALA, porphyrins or excipients of BF- 200 ALA.
History of soy or peanut allergy.
Subjects with sunburn within illumination areas (reassessment of subjects is allowed once if the sunburn is expected to resolve within the screening period. Reassessment can be done on the day of the actual treatment.).
Clinically significant medical conditions making implementation of the protocol or interpretation of the study results difficult or impairing subjects' safety such as:
1. Presence of porphyria or known photodermatoses
2. Known diagnosis of human immunodeficiency virus (HIV) based on clinical history
3. Metastatic tumor or tumor with high probability of metastasis
4. Infiltrating skin neoplasia (suspected or known)
5. Unstable cardiovascular disease (New York Heart Association [NYHA] class III, IV)
6. Unstable hematologic (including Myelodysplastic syndrome), hepatic, renal, neurologic, or endocrine condition
7. Unstable collagen-vascular condition
8. Unstable gastrointestinal condition
9. Immunosuppressive condition
10. Presence of clinically significant inherited or acquired coagulation defect
Clinical diagnosis of atopic dermatitis, Bowen's disease, BCC, eczema, psoriasis, rosacea, SCC, other malignant or benign tumors in the treatment field(s), or other possible confounding skin conditions (e.g. wounds, irritations, bleeding or skin infections) within or in close proximity (< 5 cm distance) to treatment field(s). (Reassessment of subjects is allowed once if wounds, irritations, bleeding or skin infections are expected to resolve within the screening period. Reassessment can be done on the day of the actual treatment.)
Presence of strong pigmentation, tattoos or any other abnormality that may impact lesion assessment or light penetration in the treatment field(s).
More than moderate smoker (e.g. > 10 cigarettes/day or equivalent).
Suspicion of drug or alcohol abuse. For the purpose of this study, alcohol abuse is defined as more than moderate alcohol consumption (> 1 drink/day for women and > 2 drinks/day for men).
Physical treatment of malignant or benign tumors of the skin within the treatment field(s) and at a distance of < 5 cm to the treatment field(s) during the last 4 weeks prior to screening.
Any therapy such as cryotherapy, laser therapy, electrodessication, surgical removal of lesions, curettage, or treatment with chemical peels such as trichloroacetic acid within the treatment field(s), or within a radius less than 5 cm away from the treatment field(s) 4 weeks prior to screening.
Any topical medical treatment of the skin within the designated time period below:
1. Topical treatment with ALA or methyl-aminolevulinate (MAL) or an investigational drug in- and outside the treatment field(s) within 8 weeks prior to screening.
2. Topical treatment with immunomodulatory/immunosuppressive antiinflammatory, or cytotoxic agents inside the treatment field(s) or within a radius less than 5 cm away from the treatment field(s) within 8 weeks prior to screening.
3. Start of topical administration of medication with hypericin or other drugs with phototoxic or photoallergic potential in- and outside the treatment field(s) within 8 weeks prior to screening. Subjects may, however, be eligible if such medication was applied for more than 8 weeks prior to screening visit without evidence of an actual phototoxic/photoallergic reaction.
Any use of the below specified systemic treatments within the designated periods:
1. Use of cytotoxic drugs within 24 weeks, immunomodulators or immunosuppressive therapies or use of ALA or ALA-esters (e.g. MAL) within 12 weeks, investigational drugs or drugs known to have major organ toxicity within 8 weeks, interferon or corticosteroids (oral or injectable) within 6 weeks prior to screening.
2. Start of intake of medication with hypericin or systemically-acting drugs with phototoxic or photoallergic potential within 8 weeks prior to screening. Subjects may, however, be eligible if such medication was taken in or applied for more than 8 weeks prior to screening visit without evidence of an actual phototoxic/photoallergic reaction.
Laboratory values outside the reference range that are clinically significant in the opinion of the investigator (e.g., suggesting an unknown disease and requiring further clinical evaluation according to investigator), especially aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (gamma- GT).
Impaired renal function (Glomerular filtration rate below 50 mL/min/1.73m² estimated by Modification of Diet in Renal Disease equation (MDRD)).
Positive test for HIV antibodies, Hepatitis B-virus surface antigen (HBsAg) or positive Anti-hepatitis C-virus antibody (Anti-HCV) test.
Significant blood donation or blood loss (≥ 500 mL) within three months prior to Visit 2.
Breast-feeding women.
Subject unlikely to comply with the protocol, e.g. inability to return for visits, unlikely to complete the study, or inappropriate in the opinion of the investigator.
Prior participation in the study (participation is defined as having been screened).
A member of study site staff or sponsor staff directly involved in the conduct of the protocol or a close relative thereof.
Simultaneous participation in a further clinical study.

Reassessment of subjects is allowed once if sunburn, wounds, irritations, bleeding or skin infections detected at Visit 1 are expected to resolve within the screening period.

Reassessment can be done on the day of the actual treatment.

Dosing day exclusion criteria:

Febrile or infectious illness within 7 days prior to Visit 2.
Subjects with sunburn, wounds, irritations, bleeding or other confounding skin conditions within illumination areas at Visit 2.
Use of topical NSAIDs inside and outside the treatment field(s) or systemic intake of NSAIDs within 7 days prior to Visit 2.

In case a subject meets one of the dosing day exclusion criteria, Visit 2 can be rescheduled once within 14 days. Meeting any of the dosing day exclusion criteria on the rescheduled visit will lead to discontinuation of the trial.

Facility	Status	City	State	ZIP	Country	Contacts
DermResearch Inc.		Austin	Texas	78759	United States

PubMed Identifier	Type	Citation	Retractions
34633154	Derived	Novak B, DuBois J, Chahrour O, Papusha T, Hirt S, Philippi T, Zogel C, Osenberg K, Schmitz B, Lubbert H. Clinical Pharmacokinetics and Safety of a 10% Aminolevulinic Acid Hydrochloride Nanoemulsion Gel (BF-200 ALA) in Photodynamic Therapy of Patients Extensively Affected With Actinic Keratosis: Results of 2 Maximal Usage Pharmacokinetic Trials. Clin Pharmacol Drug Dev. 2022 Apr;11(4):535-550. doi: 10.1002/cpdd.1023. Epub 2021 Oct 11.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	BF-200 ALA (Stratum Face/Scalp and Stratum Periphery)	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jan 17, 2020	Aug 18, 2021

Arm/Group Information

ID	Title	Description
BG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed
BG001	Stratum: Periphery	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG00016 BG00116 BG00232

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Assessment of Baseline-adjusted Plasma Concentration-time Curves for ALA After a Single PDT Treatment Applying 3 Tubes of BF-200 ALA in Conjunction With the BF-RhodoLED® Under Maximal Use Conditions in Subjects With Mild to Severe Actinic Keratosis.

Blood samples for ALA analysis for each subject were collected, starting at Visit 1 and then 0.5h prior to BF-200 ALA application for up to 10h afterwards. The concentrations of ALA in plasma were measured by an analytical laboratory using validated, internally standardized liquid chromatography-tandem mass spectrometry methods.

ALA Pharmacokinetic Set (PKS ALA): includes all subjects who had at least one evaluable pre-dose and post-dose pharmacokinetic sample (i.e., samples taken after the application of BF-200 ALA); a pre-dose/post-dose sample was regarded evaluable if the plasma concentration was at or above LLOQ.

Posted

Geometric Mean

Standard Deviation

ng/mL

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed
OG001	Stratum: Periphery	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Units	Counts
Participants	OG00016 OG00116

Title

Denominators

Categories

0.5h

Title	Measurements
	OG0008.904± 3.3502 OG00110.21± 5.2811

Title	Measurements
	OG000

Primary

Assessment of Baseline-adjusted Plasma Concentration-time Curves for PpIX After a Single PDT Treatment Applying 3 Tubes of BF-200 ALA in Conjunction With the BF-RhodoLED® Under Maximal Use Conditions in Subjects With Mild to Severe Actinic Keratosis.

Blood samples for PpIX analysis for each subject were collected, starting at Visit 1 and then 0.5h prior to BF-200 ALA application for up to 10h afterwards. The concentrations of PpIX in plasma were measured by an analytical laboratory using validated, internally standardized liquid chromatography-tandem mass spectrometry methods.

PpIX Pharmacokinetic Set (PKS PpIX): includes all subjects who had at least one evaluable pre-dose and post-dose pharmacokinetic sample (i.e., samples taken after the application of BF-200 ALA); a pre-dose/post-dose sample was regarded evaluable if the plasma concentration was at or above LLOQ.

Posted

Geometric Mean

Standard Deviation

ng/mL

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Evaluation of Baseline-adjusted Pharmacokinetic Parameters of ALA.

Parameter: AUC(0-t) (Area Under Curve); area under the baseline-adjusted plasma concentration-time curve from time zero to the last sampling time point at which the concentration was at or above lower limit of quantification; t(last) is defined as the last value >0 after baseline adjustment.

Posted

Geometric Mean

Standard Deviation

h*ng/mL

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Evaluation of Baseline-adjusted Pharmacokinetic Parameters of ALA.

Parameter: AUC(0-∞) (Area Under Curve); area under the baseline-adjusted plasma concentration-time data extrapolated to infinity

Posted

Geometric Mean

Standard Deviation

h*ng/mL

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Evaluation of Baseline-adjusted Pharmacokinetic Parameters of ALA.

Parameter: %AUC(t-∞) (Area Under Curve); proportion of extrapolated part

Posted

Geometric Mean

Standard Deviation

percentage of AUC (0-∞)

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Evaluation of Baseline-adjusted Pharmacokinetic Parameters of ALA.

Parameter: Cmax (Maximum Plasma Concentration); observed maximum baseline-adjusted plasma concentration

Posted

Geometric Mean

Standard Deviation

ng/mL

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Evaluation of Baseline-adjusted Pharmacokinetic Parameters of ALA.

Parameter: Tmax (time to reach Cmax)

Posted

Median

Full Range

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed
OG001	Stratum: Periphery

Secondary

Evaluation of Baseline-adjusted Pharmacokinetic Parameters of ALA.

Parameter: λz (Elimination Rate Constant); λz denotes the terminal rate constant estimated by linear regression analysis from a range of concentrations in the terminal phase estimated for each treatment and subject by log-linear regression from the linear portion of the logarithmic transformed concentration-time plot. The algorithm will start with the last 3 points with quantifiable concentrations and increases the number of involved points by 1 until the time point after Cmax restricted on time points after removing of the BF-200 ALA gel (all PK samples after the gel is wiped off [after 3h±10 min); λz was only determined in subjects in which the log-linear terminal phase could clearly be defined. Resulting unreliable parameters were flagged accordingly and not used in descriptive statistics. If any pharmacokinetic parameter should have been classified as unreliable, all calculations that use this parameter were considered missing.](streamdown:incomplete-link)

Posted

Geometric Mean

Standard Deviation

1/h

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Evaluation of Baseline-adjusted Pharmacokinetic Parameters of ALA.

Parameter: t1/2 (apparent terminal half-life); calculated by ln2/λz; t1/2 was only determined in subjects in which the log-linear terminal phase could clearly be defined. Resulting unreliable parameters were flagged accordingly and not used in descriptive statistics. If any pharmacokinetic parameter should have been classified as unreliable, all calculations that use this parameter were considered missing.

Posted

Geometric Mean

Standard Deviation

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Evaluation of Baseline-adjusted Pharmacokinetic Parameters of PpIX.

Posted

Geometric Mean

Standard Deviation

h*ng/mL

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Evaluation of Baseline-adjusted Pharmacokinetic Parameters of PpIX.

Parameter: AUC(0-∞) (Area Under Curve); area under the baseline-adjusted plasma concentration-time data extrapolated to infinity

Posted

Geometric Mean

Standard Deviation

h*ng/mL

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Evaluation of Baseline-adjusted Pharmacokinetic Parameters of PpIX.

Parameter: %AUC(t-∞) (Area Under Curve); proportion of extrapolated part

Posted

Geometric Mean

Standard Deviation

percentage of AUC (0-∞)

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Evaluation of Baseline-adjusted Pharmacokinetic Parameters of PpIX.

Parameter: Cmax (Maximum Plasma Concentration); observed maximum baseline-adjusted plasma concentration

Posted

Geometric Mean

Standard Deviation

ng/mL

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Evaluation of Baseline-adjusted Pharmacokinetic Parameters of PpIX.

Parameter: Tmax (time to reach Cmax)

Posted

Median

Full Range

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed
OG001	Stratum: Periphery

Secondary

Evaluation of Baseline-adjusted Pharmacokinetic Parameters of PpIX.

Posted

Geometric Mean

Standard Deviation

1/h

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Evaluation of Baseline-adjusted Pharmacokinetic Parameters of PpIX.

Posted

Geometric Mean

Standard Deviation

On treatment day (day 0): 0.5, 1, 1.5, 2, 2.5, 3*, 3.5, 4, 5, 6, 8, 10 hours post-dose (*prior to illumination)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Assessment of the Frequency and Severity of All Treatment-emergent Adverse Events (TEAEs), Including Serious Adverse Events (SAEs) in Response to PDT With BF-200 ALA Under Maximal Use Conditions.

Frequency of treatment-emergent adverse events (TEAEs),including serious adverse events (SAEs).

Safety analysis set (SAF): includes all subjects who underwent at least one of the following treatment procedures: preparation of the treatment field(s), application of BF-200 ALA, or illumination. If the conduct of any treatment procedures was not certain, the subject was to be included in the SAF.

Posted

Count of Participants

Participants

On treatment day until end of study approximately 4 weeks after treatment day (day 0)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Assessment of Pain Intensity at the Application Site in Response to PDT With BF-200 ALA Under Maximal Use Conditions Using an 11-point Numeric Rating Scale (NRS-11), Where a Score of 0 Means "no Pain" and a Score of 10 Means "Worst Imaginable Pain".

Assessment of pain at the application site using an 11-point Numeric Rating Scale (NRS-11) ranging from 0 (no pain) to 10 (worst imaginable pain)

Posted

Mean

Standard Deviation

score on a scale

On treatment day until end of study approximately 4 weeks after treatment day (day 0)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Assessment of Frequency and Severity of Application Site Discomfort in Response to PDT With BF-200 ALA Under Maximal Use Conditions.

Application site reactions: discomfort (burning, pain, itching, stinging, warmth, others)

Posted

Count of Participants

Participants

On treatment day until end of study approximately 4 weeks after treatment day (day 0)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Secondary

Assessment of Frequency and Severity of Application Site Skin Reactions in Response to PDT With BF-200 ALA Under Maximal Use Conditions.

Application site reactions: skin reactions (erythema, edema, induration, vesicles, erosion, ulceration, scaling/flaking, scabbing/crusting, discharge/exudate, others); maximum severity of AE: mild, moderate, or severe

Posted

Count of Participants

Participants

On treatment day until end of study approximately 4 weeks after treatment day (day 0)

ID	Title	Description
OG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Stratum: Face/Scalp	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed	0	16	0	16	16	16
EG001	Stratum: Periphery	• Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) • Each subject received three entire tubes of the IMP (2 g each, containing 156 mg ALA), resulting in a total dose of 468 mg ALA (free base) • The amount was sufficient to cover one treatment field (continuous field or discontinuous field with several patches), totaling approx. 60 cm² with BF-200 ALA gel at a thickness of approx. 1 mm • Treatment field(s) could be located on either the face/scalp or in the periphery (neck/trunk/extremities) excluding the genitalia (minimal distance of about 1 cm) • IMP dried for approx. 10 min • Subjects had to stay in a well-tempered environment during 3h incubation under light-blocking, occlusive dressing • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED® (10 min; 37 J/cm²) • In case of discontinuous treatment field(s), two BF-RhodoLED® lamps were used simultaneously • One single PDT was performed	0	16	0	16	16	16

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Application site erythema	General disorders	MedDRA 23.0	Systematic Assessment	EG00018 events16 affected16 at risk EG00119 events16 affected16 at risk
Application site exfoliation	General disorders	MedDRA 23.0	Systematic Assessment	EG00013 events10 affected16 at risk EG0014 events3 affected16 at risk
Application site hyperaesthesia	General disorders	MedDRA 23.0	Systematic Assessment	EG0003 events2 affected16 at risk EG0012 events1 affected16 at risk
Application site induration	General disorders	MedDRA 23.0	Systematic Assessment	EG0003 events2 affected16 at risk EG0012 events2 affected16 at risk
Application site oedema	General disorders	MedDRA 23.0	Systematic Assessment	EG00018 events16 affected16 at risk EG00110 events9 affected16 at risk
Application site pain	General disorders	MedDRA 23.0	Systematic Assessment	EG00063 events16 affected16 at risk EG00144 events16 affected16 at risk
Application site paraesthesia	General disorders	MedDRA 23.0	Systematic Assessment	EG0005 events4 affected16 at risk EG0012 events1 affected16 at risk
Application site pruritus	General disorders	MedDRA 23.0	Systematic Assessment	EG0004 events4 affected16 at risk EG0017 events6 affected16 at risk
Application site scab	General disorders	MedDRA 23.0	Systematic Assessment	EG0006 events5 affected16 at risk EG0016 events6 affected16 at risk
Application site vesicles	General disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected16 at risk EG0014 events2 affected16 at risk
Application site warmth	General disorders	MedDRA 23.0	Systematic Assessment	EG0005 events4 affected16 at risk EG0011 events1 affected16 at risk
Application site discharge	General disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected16 at risk EG0010 events0 affected16 at risk
Application site discolouration	General disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected16 at risk EG0011 events1 affected16 at risk
Application site erosion	General disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected16 at risk EG0011 events1 affected16 at risk
Application site fissure	General disorders	MedDRA 23.0	Systematic Assessment	EG0002 events1 affected16 at risk EG0012 events1 affected16 at risk
Application site haemorrhage	General disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected16 at risk EG0010 events0 affected16 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected16 at risk EG0011 events1 affected16 at risk
Nausea	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected16 at risk EG0011 events1 affected16 at risk
Seasonal allergy	Immune system disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected16 at risk EG0010 events0 affected16 at risk
Application site pustules	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0002 events1 affected16 at risk EG0010 events0 affected16 at risk
Bacteriuria	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected16 at risk EG0010 events0 affected16 at risk
COVID-19	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected16 at risk EG0010 events0 affected16 at risk
Pyuria	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected16 at risk EG0010 events0 affected16 at risk
Seborrhoeic keratosis	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected16 at risk EG0011 events1 affected16 at risk
Headache	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected16 at risk EG0010 events0 affected16 at risk
Sinus headache	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected16 at risk EG0010 events0 affected16 at risk
Actinic keratosis	Skin and subcutaneous tissue disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected16 at risk EG0011 events1 affected16 at risk
Alopecia	Skin and subcutaneous tissue disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected16 at risk EG0010 events0 affected16 at risk

ID	Term
D011230	Precancerous Conditions
D009369	Neoplasms
D007642	Keratosis
D012871	Skin Diseases
D017437	Skin and Connective Tissue Diseases