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Irradiation with visible blue light (wavelength 400-495 nm) is a promising, effective, and safe new treatment option for chronic inflammatory skin diseases such as psoriasis and atopic dermatitis.
We will perform a multicenter, placebo-controlled, double-blinded, 3-armed, prospective, randomized controlled trial to investigate the efficacy and safety of full-body blue light devices (wavelengths: 415 nm and 450 nm) compared with that of placebo irradiation for the treatment of atopic dermatitis.
We are planning to enroll a total of 150 patients at the University hospitals in Göttingen (Germany), Marburg (Germany), and Geneva (Switzerland).
The trial was approved by the lead ethics committee of the medical faculty of the University of Göttingen (21/11/16). Further approvals were obtained from local and federal authorities (ethics committee Marburg, Cantonal Commission for Research Ethics Geneva, Suisse Medic, and Bundesinstitut für Arzneimittel und Medizinprodukte).
We will disseminate the results in a peer-reviewed journal.
ClinicalTrials.gov NCT03085303; https://clinicaltrials.gov/ct2/show/NCT03085303 (Archived by WebCite at http://www.webcitation.org/73ucqkkA1)
DERR1-10.2196/11911
Atopic dermatitis is a common chronic inflammatory disease of the skin with a lifetime prevalence of 10%-20% in adults in developed countries [
As atopic dermatitis is a chronic disease with an unpredictable and often relapsing course, long-term control is necessary [
Clinical data on blue light in chronic inflammatory skin diseases are scarce. Psoriasis and eczema have been the exclusive indications for comprehensive clinical trials in the past. Regarding eczema, Keemss et al [
Other smaller studies investigated the effect of blue light on patients with psoriasis. Pfaff et al [
AD-Blue trial is a multicenter, placebo-controlled, double- blinded, 3-armed, prospective, randomized controlled trial (European Database on Medical Devices #CIV-16-11-017565 and ClinicalTrials.gov NCT03085303). We designed the clinical study following the Standard Protocol Items: Recommendations for Interventional Trials guidelines (see
The primary objective is to estimate the efficacy of irradiation with blue light (415 nm and 450 nm) compared with placebo irradiation in adult patients with atopic dermatitis, determined using multiple clinical scores, such as EASI and SCORAD. Secondary objectives comprise the assessment of safety, tolerability, and satisfaction with irradiation with blue light as well as the time until treatment response under therapy and the duration of response after the last irradiation.
The primary endpoint is to determine the change from baseline in EASI in a comparison between treatment arms and placebo arm at the end of treatment. Secondary endpoints include the change from baseline in SCORAD, PO-SCORAD, visual analog scale of itch, DLQI, and IGA scores; the proportion of patients achieving 50% reduction from baseline EASI score (response); the so far mentioned endpoints at follow-up; and time until treatment response. The following safety endpoints will be addressed: change from baseline in hyperpigmentation of treated skin exposed to blue light and control as well as AEs (serious and nonserious), adverse device events (serious and nonserious), and device deficiencies.
A total of 150 patients with atopic dermatitis will be recruited at 3 sites: Geneva, Marburg, and Göttingen. The recruitment will be independent of the severity of disease and is limited to 50.0% (75/150) at each site. A sample size of 50 patients per group will have 84% power to detect a mean effect size of 0.6.
The first enrollment took place in March 2017. The study duration per patient is 13 weeks (1 week of screening, 8 weeks of irradiation, and 4 weeks of follow-up), and the estimated total time frame for recruitment of 150 patients is 14 months (last visit of the last patient estimated to be in August 2018). During July to September, no irradiations will take place due to the possible improvement of disease severity linked to the increased natural sun exposure.
Patients aged 18-75 years with atopic dermatitis according to the UK criteria of atopic dermatitis [
We will prohibit the following concomitant medication within a certain timeframe before and during the study: systemic immunosuppression treatment such as glucocorticoids, cyclosporine, azathioprine, and mycophenolate mofetil (within 8 weeks prior to baseline visit); UV irradiation treatment (within 4 weeks prior to baseline visit); topical steroids or calcineurin inhibitors (within 2 weeks prior to baseline visit); and photosensitizing medication and colors on the patient’s skin (within 3 days prior to baseline visit). Active agent-free lipid balancing creams (Unguentum leniens) will be allowed during the trial and handed out on request.
We will investigate FBB-CT01 devices (Philips; Aachen, Germany; not Conformité Européene, CE, marked) with LEDs emitting blue light (
415 nm device: Device equipped with 415 nm wavelength LEDs. Light output=40 mW/cm2. Light module equipped with fans.
450 nm device: Device equipped with 450 nm wavelength LEDs. Light output=40 mW/cm2. Light module equipped with fans.
Placebo device: Device equipped with 450 nm wavelength LEDs. Light output=0.2 mW/cm2. Light module without fans.
The devices are on lock wheels for easy transportation. We will administer phototherapeutic light for 15 minutes to each side of the body of the patient (30 minutes in total for both sides) who will lie flat on a treatment table. We will provide specific protective goggles to filter the blue color of the light. Once the user presses the ON button to switch on the device, all treatment LEDs will be on. If the user needs to stop the treatment, he or she will either press the OFF button or, in case of an emergency, the “emergency stop” button.
We will randomize 150 patients diagnosed with atopic dermatitis 1:1:1 to arm 1 (irradiation for 30 minutes at 415 nm wavelength), arm 2 (irradiation for 30 minutes at 450 nm wavelength), and arm 3 (irradiation for 30 minutes at low-dose, placebo). We will stratify randomization by study site and initial EASI score (assessed during screening visit) with permuted and variable block sizes. For each strata combination, a list of separate randomization sequences will be generated using SAS 9.3 (Cary, NC). Irradiation will be scheduled 3 times a week for 8 weeks. Participants will be followed up for 4 weeks after the last irradiation. Patients will be blinded by wearing tinted protective goggles that disenable the distinction of different wavelengths of light. Medical doctors will examine patients in rooms other than those equipped with the investigational medical devices. These examiners are blinded and are, therefore, not involved in the preparation and process of irradiation. If the safety of an enrolled patient is potentially jeopardized, the investigator can break the blinding of the treatment. According to the predefined study schedule, we will measure skin pigmentation with a mexameter; take photos and blood samples; measure blood pressure; and gather data on Fitzpatrick skin type, DLQI, itch on visual analog scale, SCORAD, IGA, EASI, and PO-SCORAD scores. Detailed information on assessments is depicted in the study schedule (
No patients or public were involved in the design of this study.
Design of the FBB-CT01 device (415 nm and 450 nm). The patient lies on the treatment table and receives treatment from the light engine above.
The primary analysis will be performed based on the full analysis set following the intention-to-treat principle. Dropouts during first 4 weeks of treatment will be replaced. Patients missing more than 5 irradiation appointments in total until day 25 (inclusive) or more than 3 consecutive irradiation appointments until day 25 (inclusive) will be considered dropouts and will be replaced. Dropouts after day 25 of the study protocol will not be replaced and will be analyzed in the intention-to-treat population. Sensitivity analysis will be done on the per-protocol population. The difference between the end of treatment after 8 weeks and baseline in primary effectiveness endpoint EASI will be analyzed using pairwise 2-sample
The two comparisons, namely, 415 nm versus placebo and 450 nm versus placebo will be evaluated equally. To address the multiplicity, a success will be declared if both comparisons are statistically significant at an alpha level of .05 or if one of these two is statistically significant with respect to half of alpha at .025.
The two risk differences between one of each blue light irradiation treatments against placebo of the rates of patients with at least one device-related adverse event (rated as possible, probable, or certain) will be compared using asymptotic Wald test of noninferiority for the risk difference. Missing values for the primary and secondary endpoints will be replaced using proper single regression methods (IVEware; University of Michigan, Ann Arbor, MI). Besides the scores (such as EASI scores), the study site, study visits with the documented EASI score, treatment group, gender, age, hand out of topical emollient, and Fitzpatrick skin type will be included in the regression models. In safety analysis, per-protocol analysis, and explorative analysis, missing values will not be replaced.
After the completion of the treatment phase of about 75 patients, first, the EASI score difference between the end of treatment and baseline and, second, the rates of device-related AEs will be analyzed descriptively using
This investigation will be performed according to the Declaration of Helsinki [
During the screening visit and preceding any study-mandated procedure, the patient will receive a copy of the written patient information sheet containing a complete and comprehensive explanation of the significance, nature, extent, and possible risks of the study and the statement that the patient is free to withdraw from the study at any time without any negative consequences. In addition, a physician will conduct an oral information session during which the patient will be given sufficient time and opportunity to clarify any questions. After this, a written informed consent will be given to the patients for a dated signature. After signature, the patient will receive a copy of the signed consent form. In addition, the patients will be asked to grant consent for taking blood and skin samples for additional investigations outside the current clinical trial. This is not mandatory and does not affect clinical trial participation in general.
Foreseeable AEs include thermal discomfort during the irradiation and increased skin pigmentation, which we expect to be of a very mild nature as experienced in previous trials. Due to the absence of UV light in our devices, we do not expect dermatitis solaris (sunburn) or an increased risk for melanoma or nonmelanoma skin cancer.
Unexpected physical accidents during the irradiation procedure itself (eg, the patient falling off the examination bed or a deficient device harming participants’ physical integrity) are possible out of general considerations. The non-CE mark investigational medical devices are classified as Class IIa according to Annex IX of the Directive 93/42/EEC and as Risk Group 2 devices according to EN 60601-2-57. They have been approved by competent federal authorities (BfArM, Suisse Medic). Precautions have been taken by means of risk management, testing, and protocol design to protect the health and safety of the patients and personnel participating in the clinical study. All AEs will be recorded and documented. Serious AEs will be reported in accordance with the appropriate legal regulations (Medizinprodukte-Sicherheitsplanverordnung). Due to the well-documented efficacy of blue light treatment in psoriasis and eczema, clinical benefits include an improvement in objective disease severity and quality of life (less itching or less insomnia expected).
In summary, blue light has the potential to improve inflammatory skin diseases. Associated risks are rare, mild, and transitory. After re-evaluation of the risks, the overall residual risk has been concluded to be satisfactory. As an overall result, we conclude that the benefits for the patients outweigh residual risk, thereby justifying the introduction of the device.
The project was funded by Philips Light & Health, and enrollment was completed in May 2018. Data analysis is currently underway, and the first results are expected to be submitted for publication in January 2019.
This is the first international, multicenter, randomized controlled trial investigating the effect of treatment with FBB light devices in patients with atopic dermatitis. A broad range of validated outcome measures has been applied to account for objective and subjective symptoms. This is an investigator-initiated trial with the design developed at the academic institutions. However, clinical heterogeneity and placebo effects may dilute the intervention’s effects.
SPIRIT Checklist.
Study schedule of assessments.
adverse event
Bundesinstitut für Arzneimittel und Medizinprodukte
Dermatology Life Quality Index
Eczema Area and Severity Index
full-body blue
Investigator’s Global Assessment
International Organization for Standardization
light-emitting diode
European Medical Device Vigilance System
Patient-Oriented-SCORing Atopic Dermatitis
SCORing Atopic Dermatitis
ultraviolet
We are very thankful for the excellent handling, assistance, and support in developing this study protocol by Florian Walker, Jutta Heinrich, and Carsten Gavenis (Clinical Trials Unit, University Medical Centre Göttingen, Göttingen, Germany).
This study is fully sponsored by Philips Light & Health, High Tech Campus 5, 5656AE Eindhoven, The Netherlands. The irradiation devices were developed and built by the sponsor. Since the sponsor’s team does not include any physicians, the study design was developed by the academic physicians. The technical details of the irradiation devices were amended by the sponsor. The study protocol was finally discussed and approved by all authors of this manuscript including employees of the sponsor.
All authors were involved in planning of this study. MPS is the lead investigator. CK, MPS, and TB wrote the first draft of this manuscript. CK, VPN, SP, HJL, WHB, WP, MPS, and TB were involved in data collection, manuscript review and critique, and final approval of the manuscript. JL and MB were involved in the manuscript review, critique, and final approval.
MB and JL are employees of Philips Light & Health.