A Non-randomized, Open-label, Multicenter Study to Evaluate the Safety and Tolerability of 10% Aminolevulinic Acid Gel in the Expanded Field-directed Treatment of Actinic Keratosis on the Face and Scalp with Red Light Photodynamic Therapy

J Clin Aesthet Dermatol. 2025;18(4):44–50.

by Joel L. Cohen, MD; John H. Tu, MD, MS; Megan P. Couvillion, MD, MS; S. Sasha Jazayeri, MD; Nathalie C. Zeitouni, MDCM, FRCPC; Sherrif F. Ibrahim, MD, PhD; Edward L. Lain, MD, MBA, FAAD; C. William Hanke, MD, MPH; Corinna Zogel, PhD; Beate Schmitz, PhD; Marie-Theres Zeuner, PhD; and Todd Schlesinger, MD, FAAD

Dr. Cohen is with AboutSkin Research in Greenwood Village, Colorado. Dr. Tu is with Skin Search of Rochester in Rochester, New York. Dr. Couvillion is with the Austin Institute for Clinical Research in Houston, Texas. Dr. Jazayeri is with Alliance Dermatology and Mohs Center in Phoenix, Arizona. Dr. Zeitouni is with Medical Dermatology Specialists Phoenix in Phoenix, Arizona. Dr. Ibrahim is with Rochester Dermatologic Surgery in Victor, New York. Dr. Lain is with the Austin Institute for Clinical Research in Pflugerville, Texas. Dr. Hanke is with Laser and Skin Surgery Center of Indiana in Indianapolis, Indiana. Drs. Zogel, Schmitz, and Zeuner are with Biofrontera Discovery GmbH in Leverkusen, Germany. Dr. Schlesinger is with the Clinical Research Center of the Carolinas in Charleston, South Carolina.

FUNDING: Funding was provided by Biofrontera Bioscience GmbH. 

DISCLOSURES: Dr. Cohen has served as a clinical research principal investigator as well as a consultant for Biofrontera. Dr. Couvillion is an investigator for AbbVie, Alumis, AnaptysBio, ArcutisBiotherapeutics, Biofrontera Bioscience GmbH, Cara Therapeutics, Castle Biosciences, Concert Pharmaceuticals, Dr. Reddy’s Laboratories, Eirion Therapeutics, Incyte, Janssen Biotech, Nielsen Bioscience Inc., Ortho Dermatologics, Timber Pharmaceuticals, TrialSpark, Inc., VeraDermics Inc., and Verrica Pharmaceuticals, is an investigator and speaker for Eli Lilly and Pfizer Inc., is a speaker for Revance therapeutics Inc., and consultant for Allergan Aesthetics and Dermavant Sciences Inc. Dr. Zeitouni is a consultant and investigator for Biofrontera Biosciences GmbH. Dr. Ibrahim is an investigator for Biofrontera Bioscience GmbH. Dr. Hanke is an investigator for AbbVie, Biofrontera Bioscience GmbH and Castle Biosciences, Inc., and received honoraria as a speaker for Sanofi/Regeneron and Sun Pharmaceutical Industries Ltd. Dr. Lain declares financial relationships with AbbVie, Aclaris Therapeutics, Allergan Inc, Almirall, Arcutis, ASLAN Pharmaceuticals, AstraZeneca, Athenix, Biopelle Inc, BioPharmX, Biorasi LLC, Bristol-Myers Squibb, Bricknell Biotech Inc., Cassiopea S.p.a., Celgene, Cellceutics, ChemoCentryx, Cutanea Life Sciences, Cutera Inc, Dermira, Dermavant Sciences Inc., Dow Pharmaceutical Sciences, Dr. Reddy’s Laboratory, Eli Lilly, Gage Development Company LLC, Galderma, Hovione, Incyte, Kadmon, La Roche-Posay, LEO Pharma, Medimmune, Menlo Therapeutics, Neothetics, Nielsen Holdings N.V, Novartis, Ortho Dermatologics, Pfizer, Promius Pharma LLC, Sebacia Inc., Sienna Labs Inc., SkinCeuticals LLC, Sol-Gel Technologies, UCB, Valeant Pharmaceuticals, and Verrica Pharmaceuticals. Drs. Zogel and Schmitz were employees of Biofrontera Bioscience GmbH at the time the study was conducted. Dr. Zeuner was an employee of Biofrontera Bioscience GmbH at the time the study results were accessible, and the manuscript was prepared. Dr. Schlesinger is a consultant and investigator for AbbVie, Almirall, Biofrontera Bioscience GmbH, Galderma and a consultant for SUN Pharma. Drs. Tu and Jazayeri have no conflicts of interest to report. Parts of the data were presented at the 44th Annual Fall Clinical Dermatology Conference® (October 2024).

ABSTRACT: Objective: Dermatologists regularly encounter patients having expanded fields with numerous actinic keratosis (AK) lesions on the face and scalp. Field-directed red light photodynamic therapy (PDT) is a well-established treatment, yet published data on the safety of PDT on large areas is scarce. We aimed to evaluate the safety and tolerability of red light PDT in treating expanded AK fields on the face and scalp. Methods: This was a non-randomized, open-label, multicenter study. After lesion preparation, 6g of 10% aminolevulinic acid (ALA) gel were applied to the treatment field (60 cm²) and incubated for three hours under a light-blocking, occlusive dressing before 10-minute illumination with a red light lamp (~635nm, 37 J/cm²). Safety and tolerability were assessed throughout the study. Results: All participants (n=100) had adverse reactions. No previously unknown effects, serious adverse events, or deaths were reported. The most frequent application site reactions were pain/burning (96.0%), exfoliation (87.0%), and erythema (86.0%). Most treatment-emergent adverse events were of mild to moderate severity and lasted slightly longer compared to those experienced after treatment of smaller areas. The mean maximum pain during PDT was 7.4±2.1 on an 11-point numeric rating scale. A transient increase in blood pressure on the day that PDT was performed was not clinically significant. Limitations: Although the allowed use of pain-reducing measures might have influenced evaluation of pain, it reflects how the procedure is managed in current practice. Conclusion: PDT with 10% ALA gel and red light illumination on an expanded treatment field was generally well tolerated.

Keywords: Photodynamic therapy, 10% ALA gel, BF-200 ALA, red light, actinic keratosis, actinic keratoses, RhodoLED, clinical research, safety, aminolevulinic acid

Introduction

Actinic keratoses (AKs) result from atypical proliferating keratinocytes in the epidermis of the skin and are considered a consequence of cumulative ultraviolet (UV) damage. With the prevalence of the disease rising,¹ the burden on the healthcare system is increasing.^2,3

AKs are an early precursor form of invasive cutaneous squamous cell carcinoma (SCC).^4,5 Multiple AK lesions^6,7 and time since initial diagnosis⁸ increase the risk of progression. In addition to clinically distinctive lesions which appear as rough, reddish or scaly patches, subclinical precancerous changes can occur in the field around those lesions. As AKs of all severity grades have a risk of progression to SCC,⁹ international guidelines strongly recommend early and field-directed treatment of AKs.^4,5,10–17 Photodynamic therapy (PDT) can be applied in a lesion- and field-directed manner^4,5,10,18 and has advantages compared to other medications or procedures.^4,5,10,19,20 PDT with 10% aminolevulinic acid (ALA) gel, has demonstrated excellent efficacy outcomes^20–23 including comparably favorable long-term efficacy.^24–26 A meta-analysis by Vegter et al²⁷ concluded that PDT using 10% ALA gel and narrow-spectrum red light was the most efficacious treatment option.

Depending on the protocol used, one common adverse reaction of PDT is pain, especially in larger treatment areas.²⁸ Nevertheless, most side effects of PDT resolve within a few days, and cosmetic results are favorable.²⁰

Dermatologists often face treatment of expanded fields with numerous AKs;²⁹ however, separate PDT sessions might further compromise treatment compliance and increase costs. Several sessions can be avoided if more clinical data is published on red light PDT of large AK areas^29–33 to confirm safety.^34,35

This study was performed to assess the safety and tolerability of red light PDT with 10% ALA gel in an expanded field-directed treatment of mild to severe AK on the face and scalp.

Methods

Trial design. This was a non-randomized, open-label, multicenter Phase I study to evaluate the safety and tolerability of PDT with 10% ALA gel and a narrow-spectrum red light lamp in the treatment of extended AK fields located on the face and scalp (NCT05060237). It was designed for a submission to the United States (US) Food and Drug Administration (FDA), targeting a label extension for the 10% ALA gel. The study was approved by the Institutional Review Board (IRB) and competent authority prior to start of the study and was performed according to national drug laws, Good Clinical Practice Guidelines, and the Declaration of Helsinki. Informed consent was obtained by all participants prior to any study procedure. Data was collected between December 2021 and April 2023 at nine sites in the US. The study consisted of five study visits: A screening visit within 14 days before treatment, a baseline/treatment visit, two interim visits for safety assessment approximately 7 and 14 days after PDT; and the final visit approximately 28 days after PDT.

Participants. Eligible participants were aged 18 years or older, with at least eight mild to moderate clinically confirmed AK lesions of ≥4mm in diameter (according to Olsen³⁶) on the face and/or scalp. Presence of severe AK lesions was allowed, however diagnosis of each severe lesion had to be confirmed histopathologically (2mm punch biopsy at screening; assessment performed by a central laboratory). Lesions classified as malignant or benign tumors inside or in close proximity (<10cm distance) to the treatment field led to exclusion of the participants from the study. The treatment field (continuous or in several patches) had to be located within one effective illumination area of the lamp (see specifics in the treatment section). Participants with a history of hypersensitivity to ALA or any other ingredient of 10% ALA gel, presence of porphyria, hypersensitivity to porphyrins, or a clinically significant medical condition rendering implementation of the protocol or interpretation of the study results difficult were excluded. The identities and personal data of all participants were safeguarded according to data protection regulations.

Treatment. 10% ALA gel (BF-200 ALA, Ameluz®; Biofrontera Pharma GmbH, Leverkusen, Germany) was manufactured and released according to Good Manufacturing Practice and relevant regulations and delivered in aluminum tubes containing 2g of gel. Treatment field was prepared by degreasing, removal of scabs and crusts, and debridement consisting of roughening of the surface, if applicable. Subsequently, three tubes (6g) of 10% ALA gel (total dose of 600mg ALA-HCl) were applied to the treatment field of 60cm² in an ~1mm thick layer (excluding eyes, nostrils, ears, and mouth). After three-hour incubation period under a light-blocking, occlusive dressing, the dressing and remaining gel were removed.

The treatment field was illuminated for 10 minutes using the RhodoLED® XL (~635nm red light, 37 J/cm²; Biofrontera Pharma GmbH, Leverkusen, Germany) at a treatment distance between 11 to 14cm. The maximum effective illumination area (using all 5 panels, curved configuration) is 667cm²; however, a minimum of three adjacent panels had to be used.

Assessments. At screening, medical history was documented. In addition, treatment fields were selected and target lesions (size, number, location, clinical severity)³⁶ ­were assessed. Throughout the study, safety and tolerability assessments were performed. The frequency of (serious) adverse events (AEs), treatment-emergent AEs, (TEAEs, all AEs with onset or worsening after application of 10% ALA gel) and adverse drug reactions (ADRs, TEAEs which were considered at least possibly related to treatment), including their duration and severity (mild, moderate, severe), were evaluated. AEs, TEAEs and ADRs were coded according to MedDRA Version 26.0. Application site skin reactions (assessed by the investigator) and application site discomfort (reported by the participants) were assessed during and after PDT. Immediately following PDT, the participants retrospectively rated the maximum pain during illumination on an 11-point numeric rating scale (NRS-11) ranging from 0 (no pain) to 10 (worst imaginable pain). Further, vital signs (blood pressure, heart rate, body temperature) were measured at all clinical visits. At screening and the final visit, hematology and clinical chemistry parameters were assessed, and participants were physically examined. Neurological assessments were performed at screening and repeatedly on the day that PDT was performed.

Statistical methods. Continuous data was summarized by means of descriptive statistics, ie number of participants, mean, standard deviation (SD), median, quartiles and range (minimum and maximum). Categorical variables were summarized by absolute and relative frequencies (percentages) of participants by category. Missing values were not included.

Results

Demographics. One hundred and twelve participants were assessed for eligibility, of which eight participants were excluded as screening failures and four participants withdrew their consent prior to treatment. In total, 100 participants received treatment and were analyzed for the outcomes. No participant discontinued the study. Participant and lesion characteristics at screening are summarized in Table 1.

Safety and tolerability. Frequency of AEs. All participants (n=100, 100%) experienced at least one AE. In total, 888 AEs were reported, of which 871 were TEAEs and 811 were ADRs. No serious AEs and no deaths were reported.

All participants experienced at least one ADR. Of 811 events in total, 749 were general disorders or administration site conditions. The most frequently reported ADRs at the application site (percent of participants) reflected the mode of action of PDT: pain/burning (96.0%), exfoliation (87.0%), erythema (86.0%) and pruritus (65.0%). Table 2 provides a comparison of frequently reported ADRs at the application site for treatment fields of 60cm² compared to already known ADRs for treatment fields of 20cm².³⁷ Regarding ADRs which occurred not at the application site, headache (17.0%) was the most frequently reported.

Duration of ADRs. Further, the mean duration of ADRs was analyzed by severity category (mild, moderate, severe), whereas only ADRs which occurred in at least two participants and with complete start/stop dates were analyzed. Most ADRs were of mild to moderate severity and resolved by the end of the study. Overall, the mean duration of the majority of ADRs was seven days or fewer and was rarely longer than 14 days (Figure 1). In the total study population, 29.6 percent of analyzed ADRs lasted on average four days or less, 62.9 percent lasted between 5 and 14 days, and 7.4 percent lasted over 15 days. Nausea (1.00±0.00 days), chills, (1.60±0.89 days) and application site warmth (2.13±1.75 days) were the ADRs with the shortest mean duration. Application site exfoliation (13.62±9.81 days), application site induration (15.71±29.67 days), and application site erythema (19.04±12.78 days) lasted the longest. The period of events classified as severe was longest for application site pain (1.87±3.47 days) and application site erythema (1.00±4.8 days).

Application site reactions. Application site skin reactions and application site discomfort were analyzed separately. Application site skin reactions were reported for 96.0 percent of participants (402 events). Exfoliation (117 events in 87.0% of participants), erythema (97 events in 86% of participants), and scab (58 events in 49.0% of participants) were the most frequently reported application site skin reactions. Application site discomfort was reported by 97.0 percent of participants (334 events). Pain (193 events in 96.0% of participants), pruritus (79 events in 65.0% of participants), and warmth (20 events in 17.0% of participants) were the most frequently reported application site discomfort categories.

Pain. All participants experienced pain during PDT. Overall, the mean maximum pain intensity reported on NRS-11 during PDT was 7.4±2.1 (median 8.0). The highest mean pain intensity was reported by participants treated on the scalp (n=39; 7.8±2.3) compared to face (n=40; 7.2±2.2) and face and scalp (n=21; 7.3±1.7). As pain during PDT is related to the size of the treatment area, higher pain was anticipated.Thus, different measures or medications to relieve pain were allowed. At study start, medication during illumination (eg, applied or injected fast-acting anesthetic) and/or physical measures (eg, interruption of illumination and/or cooling with an air stream and/or nebulized water) were allowed. After some participants prematurely terminated the illumination due to severe pain, and several interruptions of the illumination were documented, the study protocol was revised to include prophylactic analgesic treatment (eg, oral non-steroidal anti-inflammatory drugs, applied or injected fast-acting anesthetic). However, as prophylactic analgesic treatment might impact data integrity for pain evaluation, all pain-relieving measures were documented accordingly. Participants receiving no measure, all measures, and any of the combinations were analyzed separately (Figure 3). No relevant effect of the measures was noticeable.

Vital signs. In general, the PDT procedure had no effect on the body temperature or heart rate (Table 3). Mean blood pressure was slightly elevated prior and shortly after illumination but were normal at all following visits (Table 3, Figure 2). The highest mean values were measured within 10 minutes after illumination: The mean change from baseline was 17.3±16.5mmHg for systolic blood pressure and 7.1±9.3mmHg for diastolic blood pressure.

Other safety assessments. Whereas no clinically significant urinalysis findings were observed, two participants (2%) had clinically significant hematology (elevated liver enzymes) and clinical chemistry (elevated blood glucose) findings 22 and 29 days after PDT, which were of mild severity and considered unrelated to the treatment. Results of physical examinations and neurological assessments were normal.

Discussion

This study showed the safety and tolerability of 10% ALA gel in the expanded field-directed treatment of AK on the face and scalp with red light PDT. Moreover, its results were decisive for a recent FDA-approved label extension concerning the treatment of expanded AK fields up to 60cm² using red light PDT with up to three tubes of 10% ALA gel.

Field-directed treatments are recommended in current guidelines.^10,14,15 Several studies indicated good efficacy and tolerability for ALA-PDT on extended fields with numerous AK,^29–34 including daylight PDT.^38–41 In particular, one retrospective study assessed the tolerability of PDT with 10% ALA gel in areas ranging from 75cm² to 300cm² in 203 participants with AK. The results indicated that PDT treatment of areas larger than 20cm² is safe.³⁴ Furthermore, two maximal use studies assessed pharmacokinetics using 2g 10% ALA gel on 20cm² skin and 6g on 60cm² skin. The authors showed that a similar, minor fraction of topical ALA was systemically absorbed under both dosing regimens,³⁵ which was well below the daily rate of ALA synthesis (200–354mg).⁴²

In our study, all participants had at least one AE, which is to be expected as the therapeutic principle of PDT is based on phototoxic effects. Most ADRs were consistent with those already known to occur on treatment fields up to 20cm².^21–23,37

Although most of the ADRs and TEAEs were transient, the mean duration of ADRs was slightly prolonged compared to those experienced after treatment of smaller areas.³⁷ This can be explained by the recovery time of the large area which was treated. The duration of the recovery depends on the different stages of wound healing. These involve the removal of dead or devitalized atypical keratinocytes and epithelialization of the area.⁴³ Larger skin areas thus need longer to recover.

One of the most common side effects of PDT is pain. In general, pain starts within seconds after start of illumination, peaks usually within the first minute, and decreases gradually afterwards.⁴⁴ This should be considered when interpreting maximum pain intensities reported during PDT. Furthermore, PDT is more painful when performed on well-innervated areas of the skin, such as the face.^28,45 When compared to pain scores in areas <20cm², maximum pain during illumination was slightly higher in our study.^21–23 This might be expected, as pain during PDT presumably correlates with the size of the treatment field and the extent of the disease.²⁸ Nevertheless, the pain score in our study was lower than in another recent study with 10% ALA gel on larger areas.³⁵ In general, it might be useful to offer physical pain-relieving measures to patients: although the mean pain was not measurably influenced by the different mitigation methods, the participants were more compliant with the whole illumination duration. A psychological component, eg, feeling more secure or being taken care of, might explain the effect.

Males have been previously described as more susceptible to pain.²⁸ However, the higher rate of male participants in our study did not distort the mean maximum pain scores. Males have consistently higher rates of AKs compared to females.^46,47 In addition, the risk of developing AKs have been shown to increase significantly with age, particularly in patients with fair skin,^17,48 and a strong risk factor for the development of more than 10 AKs was baldness in males.⁴⁹ Thus, the ratio of male and female participants in our study reflect the prevalence of the disease in the studied population.

Interestingly, previous studies reported that pain and blood pressure during PDT correlate. They showed that PDT was associated with a significant increase in blood pressure both during and shortly after illumination.^50–52 The slight transient increase in blood pressure in the current study might be due to the pain experienced during illumination. Furthermore, the slight increase in blood pressure within 10 minutes prior to illumination might be due to agitation and nervousness before illumination. Aiyer et al⁵³ defined a significant increase in blood pressure as an increase in systolic blood pressure of greater than 20mmHg and an increase in diastolic blood pressure of greater than 10mmHg. Thus, according to these criteria, the average increase in systolic and diastolic blood pressure observed in the current study would not be considered clinically significant.

Conclusion

From the results of this study, it can be concluded that PDT with three tubes of 10% ALA gel and red light illumination on an expanded treatment field of 60cm² was generally well tolerated. No previously unknown side effects, serious AEs, deaths, or other clinically relevant AEs were reported during the study and no subject discontinued the study due to an AE.

Acknowledgements

We thank all clinical research staff and participants involved in the study, and Prof. Dr. Hermann Lübbert, Dr. Jon Lyons, Dr. Nicole Pospiech, and Ruth Schäning for intellectual input.

References 

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