A Randomized, Double Blind, Vehicle-controlled, Multicenter Phase II Study to Evaluate the Safety and Efficacy of BF-200 ALA (Ameluz®) and BF-RhodoLED® in the Treatment of Moderate to Severe Acne Vulgaris in Adults With Photodynamic Therapy (PDT)
The aim of this study is to test the safety and efficacy of photodynamic therapy (PDT) for the medication Ameluz® performed with the PDT-lamp BF-RhodoLED® in comparison to the respective placebo treatment for moderate to severe Acne vulgaris.
Sex: All, ages: 16 Years to any
Inclusion Criteria:
1. 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 and HIPAA form must be obtained in writing prior to starting any study procedures. Minors under 18 years of age must be accompanied by the parent(s) or legal guardian(s) at the time of consent signing. The parent(s) or legal guardian(s) must also provide informed consent/HIPAA for the subject.
2. Subjects with moderate to severe acne on the face (IGA ≥3).
3. Presence of ≥20 inflammatory and ≥20 non-inflammatory (open and closed comedones) Acne vulgaris lesions on the face (should be located within not more than 2 illumination areas) as assessed by investigator.
4. All sexes, ≥16 years of age.
5. Willingness and ability to comply with study procedures, particularly willingness to receive up to 3 PDTs within 8 to 10 weeks.
6. Subjects with good general health or with clinically stable medical conditions will be permitted to be included in the study.
7. Willingness to stop topical facial treatments other than medical cleansers (i.e. face washes etc.) at least 14 days prior to randomization visit (Visit 2, baseline) and discontinue medical cleansers in the face at least 1 week prior to randomization visit (Visit 2, baseline) and thereafter until the end of study (use of soap is allowed but the product used should not be changed during the study).
8. Females of reproductive 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. (If hormonal contraception is used, the same product and dose should be taken for at least 6 months before the first treatment and throughout the entire study.)
Exclusion Criteria:
1. Any known history of hypersensitivity to ALA, porphyrins or excipients of BF-200 ALA.
2. History of soy or peanut allergy.
3. Subjects with sunburn 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. (Reassessment of subjects is allowed once if the sunburn or other confounding skin conditions is/are expected to resolve within the screening period.
Reassessment can be done on the day of the actual treatment.)
4. Clinical diagnosis of atopic dermatitis and other cutaneous conditions (e.g. lupus erythematosus), Bowen's disease, BCC, eczema, psoriasis, acne conglobate, acne fulminans, or secondary acne (steroid-induced acne, perioral dermatitis, acne rosacea), squamous cell carcinoma, other malignant or benign tumors in the treatment field.
5. Clinically significant (CS) medical conditions making implementation of the protocol or interpretation of the study results difficult or impairing subject's safety such as:
1. Presence of photodermatoses or porphyria
2. Metastatic tumor or tumor with high probability of metastasis
3. Infiltrating skin neoplasia (suspected or known)
4. Unstable cardiovascular disease (New York Heart Association class III, IV)
5. Unstable hematologic (including Myelodysplastic syndrome), hepatic, renal, neurologic, or endocrine condition
6. Unstable collagen-vascular condition
7. Unstable gastrointestinal condition
8. Immunosuppressive condition
9. Presence of clinically significant inherited or acquired coagulation defect
6. Beard or other facial hair that might interfere with the study assessments unless subject agrees to be clean-shaven throughout the entire study period. (Reassessment of subjects is allowed once if assessment of acne lesions is impaired by facial hair at screening. Reassessment can be performed on the day of the actual treatment).
7. Facial procedures such as dermabrasion, chemical or laser peels as well as exposure to UV radiation (other than sunlight) at least 4 weeks prior to randomization visit (Visit 2, baseline).
8. Presence of strong artificial pigmentation (e.g. tattoos) or any other abnormality that may impact lesion assessment or light penetration in the treatment field.
9. Suspicion of drug or alcohol abuse.
10. Any topical medication of the skin prior to screening as defined below:
1. Topical treatment with ALA or ALA-esters (e.g. MAL) or an investigational drug in- and outside the treatment field within 8 weeks prior to screening.
2. Topical treatment with immunosuppressive, cytostatic or cytotoxic drugs inside the treatment field within 8 weeks prior to screening.
3. Start of a regular and continuous topical administration of medication with hypericin or other drugs with phototoxic or photoallergic potential inside the treatment field within 4 weeks prior to screening. Subjects may, however, be eligible if such medication was regularly applied for more than 4 weeks prior to screening visit without evidence of an actual phototoxic/photoallergic reaction or if such medication is only administered for a limited time (e.g. an antibiotic)
11. Any use of the below specified systemic treatments within the designated periods:
1. Systemic acne therapy (oral antibiotics within 8 weeks or oral isotretinoin within 6 months or start with hormonal therapy for acne within 6 months prior to Visit 2).
2. Use of cytotoxic or cytostatic drugs within 6 months, 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 glycocorticosteroids (oral or injectable) within 6 weeks prior to screening.
3. Start of long-term intake of medication with hypericin or systemically acting drugs with phototoxic or photoallergic potential within 8 weeks prior to screening. Subjects may, however, be screened and randomized if such medication was taken in or was regularly applied for more than 8 weeks prior to screening visit without evidence of an actual phototoxic/photoallergic reaction or if such a drug is only used for a limited time (e.g. an antibiotic).
12. Breast feeding women.
13. Subject unlikely to comply with protocol, e.g. inability to return for visits, unlikely to complete the study, or inappropriate in the opinion of the investigator.
14. Prior randomization in the study.
15. A member of study site staff or sponsor staff directly involved in the conduct of the protocol or a close relative thereof.
16. Simultaneous participation in a further clinical study.
17. Four or more nodular acne lesions on the face.
18. Unwillingness or inability to limit sun exposure for 48 hours post PDT treatment.
Dosing Day exclusion criteria:
1. Febrile or infectious disease within 7 days prior to PDT visits.
2. Subjects with sunburn, wounds, irritations, bleeding or other confounding skin conditions within illumination areas at PDT visits.
3. Application of topical glycocorticosteroids in- and outside the treatment field within 7 days prior to PDT visits
4. Administration of (topical or systemic) medication with phototoxic/photoallergic potential for a limited time. After discontinuing the medication, a wash out period of the medications 5-fold half-life time should be applied prior to the next PDT.Participant flow
| Milestone | 1h Incubation BF-200 ALA | 3h Incubation BF-200 ALA | 1h Incubation Vehicle | 3h Incubation Vehicle |
|---|
| Started | 42 | 36 | 21 | 21 |
| Completed | 29 | 21 | 15 | 14 |
| Not completed | 13 | 15 | 6 | 7 |
Outcome results
- Relative Change in the Number of Inflammatory Lesions (Relative Change From Baseline) 8 Weeks After the Last PDT as Assessed by Investigator. (Primary), Mean, percentage change from baseline: 1h Incubation BF-200 ALA -37.89 +/- 39.92; 3h Incubation BF-200 ALA -48.69 +/- 31.75; Vehicle (1h and 3h Incubation Pooled) -38.84 +/- 41.84
- Treatment Success Defined by a Minimum Improvement of the Modified Investigator Global Assessment (mIGA) Score by at Least 2 Assessed 8 Weeks After the Last PDT and Resulting in an mIGA Score of 0 (Clear) or 1 (Almost Clear). (Primary), Count of participants, Participants: 1h Incubation BF-200 ALA 5; 3h Incubation BF-200 ALA 7; Vehicle (1h and 3h Incubation Pooled) 8
- Absolute Change From Baseline in the Number of Lesions as Assessed by Investigator (After the Last PDT). (Secondary), Mean, lesions: 1h Incubation BF-200 ALA -9.0 +/- 12.8; 3h Incubation BF-200 ALA -18.9 +/- 13.4; Vehicle (1h and 3h Incubation Pooled) -15.2 +/- 21.7
- Percentage Change From Baseline in the Number of Lesions as Assessed by Investigator (After the Last PDT). (Secondary), Mean, percentage: 1h Incubation BF-200 ALA -37.92 +/- 45.09; 3h Incubation BF-200 ALA -55.24 +/- 28.04; Vehicle (1h and 3h Incubation Pooled) -44.05 +/- 41.12
- Absolute Change From Baseline in the Number of Lesions as Assessed by Investigator (After Each PDT). (Secondary), Mean, lesions: 1h Incubation BF-200 ALA -6.8 +/- 7.6; 3h Incubation BF-200 ALA -9.4 +/- 10.9; Vehicle (1h and 3h Incubation Pooled) -9.4 +/- 14.5
- Percentage Change From Baseline in the Number of Lesions as Assessed by Investigator (After Each PDT). (Secondary), Mean, percentage: 1h Incubation BF-200 ALA -26.02 +/- 27.26; 3h Incubation BF-200 ALA -34.72 +/- 33.34; Vehicle (1h and 3h Incubation Pooled) -30.65 +/- 34.55
- Absolute Change From Baseline in the Number of Lesions as Assessed by Investigator, Only for Responders at Visit 3 / 4 Weeks After PDT-1. (Secondary), Mean, lesions
- Percentage Change From Baseline in the Number of Lesions as Assessed by Investigator, Only for Responders at Visit 3 / 4 Weeks After PDT-1. (Secondary), Mean, percentage
- Absolute Change From Baseline in the Number of Lesions as Assessed by Investigator, Only for Responders at Visit 4b / 4 Weeks After PDT-2. (Secondary), Mean, lesions
- Percentage Change From Baseline in the Number of Lesions as Assessed by Investigator, Only for Responders at Visit 4b / 4 Weeks After PDT-2. (Secondary), Mean, percentage
- Absolute Change in the Number of Lesions as Assessed by Investigator, Only for Responders at Visit 5b / 4 Weeks After PDT-3. (Secondary), Mean, lesions: 1h Incubation BF-200 ALA ; 3h Incubation BF-200 ALA -21 +/- 0; Vehicle (1h and 3h Incubation Pooled)
- Percentage Change in the Number of Lesions as Assessed by Investigator, Only for Responders at Visit 5b / 4 Weeks After PDT-3. (Secondary), Mean, percentage: 1h Incubation BF-200 ALA ; 3h Incubation BF-200 ALA -100 +/- 0; Vehicle (1h and 3h Incubation Pooled)
- Absolute Change in the Number of Nodules & Cysts (Secondary), Mean, lesions: 1h Incubation BF-200 ALA -0.2 +/- 1.3; 3h Incubation BF-200 ALA -0.1 +/- 1.1; Vehicle (1h and 3h Incubation Pooled) -0.2 +/- 1.0
- Frequency and Severity of Adverse Events (AEs), Serious AEs (SAEs), AEs of Special Interest (AESI) and Treatment-emerged Adverse Events (TEAEs). (Other pre specified), Count of participants, Participants: 1h Incubation BF-200 ALA 40; 3h Incubation BF-200 ALA 35; Vehicle (1h and 3h Incubation Pooled) 31
- Application Site Skin Reaction Assessed by Investigator (Other pre specified), Count of participants, Participants: 1h Incubation BF-200 ALA 4; 3h Incubation BF-200 ALA 8; Vehicle (1h and 3h Incubation Pooled) 2
- Application Site Discomfort Reported by the Subjects. (Other pre specified), Count of participants, Participants: 1h Incubation BF-200 ALA 38; 3h Incubation BF-200 ALA 31; Vehicle (1h and 3h Incubation Pooled) 21
- Pain During Illumination Reported by the Subject. (Other pre specified), Mean, pain score: 1h Incubation BF-200 ALA 2.3 +/- 2.3; 3h Incubation BF-200 ALA 3.4 +/- 3.0; Vehicle (1h and 3h Incubation Pooled) 0.7 +/- 1.4
- Changes in Blood Pressure (Other pre specified), Count of participants, Participants: 1h Incubation BF-200 ALA 0; 3h Incubation BF-200 ALA 0; Vehicle (1h and 3h Incubation Pooled) 0
- Changes in Heart Rate (Other pre specified), Count of participants, Participants: 1h Incubation BF-200 ALA 0; 3h Incubation BF-200 ALA 0; Vehicle (1h and 3h Incubation Pooled) 0
- Investigation of Clinical Chemistry Parameters (Other pre specified), Count of participants, Participants: 1h Incubation BF-200 ALA 40; 3h Incubation BF-200 ALA 32; Vehicle (1h and 3h Incubation Pooled) 35
- 9 more outcome measures not shown.
Adverse events
Time frame: Collection of AEs starts with signing the informed consent documents until the final visit (up to 27 weeks).
| Arm | Deaths | Serious adverse events | Other adverse events |
|---|
| 1h Incubation BF-200 ALA | 0/42 (0.0%) | 0/42 (0.0%) | 40/42 (95.2%) |
| 3h Incubation BF-200 ALA | 0/36 (0.0%) | 1/36 (2.8%) | 35/36 (97.2%) |
| Vehicle (1h and 3h Incubation Pooled) | 0/42 (0.0%) | 1/42 (2.4%) | 31/42 (73.8%) |
Serious adverse events by term
| Term | Organ system | 1h Incubation BF-200 ALA | 3h Incubation BF-200 ALA | Vehicle (1h and 3h Incubation Pooled) |
|---|
| Appendicitis | Infections and infestations | 0/42 | 1/36 | 0/42 |
| Mania | Psychiatric disorders | 0/42 | 0/36 | 1/42 |
Other adverse events by term
| Term | Organ system | 1h Incubation BF-200 ALA | 3h Incubation BF-200 ALA | Vehicle (1h and 3h Incubation Pooled) |
|---|
| Application site discolouration | General disorders | 0/42 | 3/36 | 1/42 |
| Application site discomfort | General disorders | 3/42 | 0/36 | 3/42 |
| Application site dryness | General disorders | 7/42 | 3/36 | 2/42 |
| Application site erythema | General disorders | 15/42 | 14/36 | 11/42 |
| Application site exfoliation | General disorders | 8/42 | 8/36 | 4/42 |
| Application site oedema | General disorders | 3/42 | 8/36 | 3/42 |
| Application site pain | General disorders | 35/42 | 34/36 | 17/42 |
| Application site paraesthesia | General disorders | 6/42 | 2/36 | 3/42 |
| Application site photosensitivity reaction | General disorders | 0/42 | 3/36 | 0/42 |
| Application site pruritus | General disorders | 35/42 | 30/36 | 13/42 |
| Application site pustules | General disorders | 1/42 | 2/36 | 0/42 |
| Application site scab | General disorders | 0/42 | 2/36 | 1/42 |
| Application site warmth | General disorders | 5/42 | 1/36 | 4/42 |
| Acne | Skin and subcutaneous tissue disorders | 2/42 | 3/36 | 5/42 |