Patients screened belonged to an ambulatory clinic (IPS Universitaria, Universidad de Antioquia). All adult patients, willing to participate, between 35 and 75 years-old with symmetric facial photodamage grade 2 or 3 according to Dover's scale, were included. Exclusion criteria were nursing or pregnancy; photosensitizing disorders; active infectious skin diseases or history of herpes simplex in the face; subjects with less than 6 months of any previous rejuvenation interfering treatments; history of systemic isotretinoin in the last year; history of hypersensitivity to the active product; and subjects requiring concurrent treatment that would have interfered with the aims or assessments of the study. All patients were enrolled by one dermatologist, and each eligible patient was sequentially assigned with a number starting from 1.

This was a phase IIb-trial designed to elucidate mainly dPDT's efficacy in another indication such as skin photodamage, as it has been previously proved to be effective in the treatment of Actinic Keratosis (AKs).13,15,16

This was a unicentre Phase II, 2 arms, parallel group double blind, randomized placebo-controlled trial. Sixty participants were allocated using a ratio of 1:1 to receive either topical MAL (Metvix®, Galderma Laboratories, France) plus daylight or topical matching placebo-daylight. Allocation sequence was generated by an external statistician through a simple random sampling without replacement.18

Allocation concealment was warranted by sending the generated sequence by the statistician to the pharmacist chemist who was entailed to label and supply the active intervention and matching placebo according to a “A” or “B” code's assignment list. This coded list was thereafter sent by the pharmacist chemist to the nurse in charge of the application of the topicals who did not know the generated sequence.

The study setting and data collection was held in one center in Medellin, Colombia at an ambulatory clinic (IPS Universitaria, Universidad de Antioquia).

Study approval was obtained from the Ethics Committees/Institutional Review Boards at the participating centre. The study was designed to follow the International Conference on Harmonization of good clinical practice (GCP) guidelines, local regulations and laws, as well as to conform to Helsinki Declaration. All participants gave written informed consent before study start.

Patients were randomized to receive 1g of topical MAL or matching placebo applied to the whole face <30min before sun exposure for 2h (3 sessions, 2–4 weeks apart) in a double-blind fashion (investigators and patients).

To enhance product/placebo skin penetration a subtle abrasion with sandpaper 400 grit to the whole face, was performed. Immediately after skin abrasion, a sunscreen (Cetaphil Dermacontrol SPF30®) was applied to the entire sun-exposed area including the treatment area in both groups during daylight-PDT, to avoid sunburn. Thereafter, 15min after sunscreen application, MAL was applied.

If ambient temperature and/or sunny sky were uncomfortable for the patients, they were allowed to stay under a gazebo. Also, patients receiving placebo were allowed to receive the active intervention after data analysis and prove of efficacy.

Patients were assessed for safety one week after each session by a Dermatologist. Patients were monitored for adverse events using INVIMA's (Instituto Nacional de Vigilancia de Medicamentos y Alimentos) criteria and serious adverse events were reported in the first 24h after knowledge of the event. Pain after each session was assessed by a trained nurse.

Efficacy was evaluated after 1 month of the third (last) daylight session by another dermatologist not involved in assessing safety secondary outcomes.

Ambient temperature, daylight illuminance and irradiance were measured during all 3 sessions with LP-471 probes connected to a Delta-Ohm 9847 data-logger (Caselle di Selvazzano (PD), Italy), which performed measurements every minute starting from the time the first patient started daylight exposure, until the last patient ended exposure. This equipment was calibrated by the manufacturer.

Global and specific photodamage variables (fine lines, mottled pigmentation, sallowness, tactile roughness, coarse lines, and erythema) were measured by Dover's photodamage scale (Severity score: from 0 to 5).

Pain was measured by the quantitative visual analog scale (rated from 0 to 10).

Therapy tolerability (oozing, erythema, edema, desquamation, pigmentation and vesiculation) was measured 1 week after session 1 and session 2 (rated from 0 to 3).

In all variables, absolute and relative values were depicted, accordingly.

A minimum of 58 patients was required to give the study at least 80% power at a two-tail 5% level of significance to detect a difference in proportions of the primary outcome of 70% with MAL-dPDT vs. 30% with placebo-dPDT. These calculations were performed using Epidat®.19

All randomized patients (intention to treat (ITT) population) were included in the primary analysis. The population considered for efficacy and safety analysis consisted in all patients who received at least one dose of the study medication.

Efficacy was assessed with the calculation of the relative risk (RR) of failure with its respective 95% confidence interval. Differences between proportions of primary outcome and qualitative secondary endpoints were assessed using the χ2 test or Fisher exact test, as required. When more than 50% of cells were found to have ceros a test for comparison of proportions, was performed. Wilcoxon signed rank test was used to compare global facial photodamage and secondary outcomes severity scores on each patient, at baseline and 1 month after session 3, and the U-Mann Whitney test was used to compare pain differences.

Post hoc logistic regression to evaluate confounding and subgroup-treatment effect interactions was performed, according to gender, skin phototype, sun irradiance and time between sessions. The effect of the interventions was also evaluated adjusting for age, sun irradiance and time between sessions.

The ITT analysis included all 60 patients (54 females/6 males) for the primary outcome, according to allocation. As there were no exclusions or patients lost to follow-up, all 60 individuals were included in all other analyses.

MAL-dPDT was found to have a significantly greater treatment effect than placebo-daylight, with the majority of patients of the first group having facial improvement (15 out of 30) and 10 out of 30 having facial success vs less patients of the placebo group having facial improvement (2 out of 30) and 1 out of 30 having facial success (p=0.00). Clinical effects are shown in Figs. 2 and 3.

Figure 2.

Before and after clinical photographs. After treatment with MAL+daylight, facial skin appears lighter, with improvement of frontal and external eye wrinkles.

(0.45MB).

Figure 3.

Before and after clinical photographs. After treatment with MAL+daylight, facial skin appears lighter, with improvement of frontal wrinkles and of nasolabial folds and perioral wrinkles.

(0.5MB).

For RR calculation, the number of whole faces that succeeded was added to the number of whole faces that improved. The risk of failure was lower in the MAL-dPDT group than in the placebo-daylight group (RR: 0.18; 95% CI: 0.08–0.41). The number needed to treat (NNT) to have a benefit from the experimental therapy was 1 (95% CI: 1.11–1.78).

After randomization, one patient was eligible according to her global facial photodamage, but he did not meet the age criteria (she was 33 years-old). However, she completed the study and was analyzed accordingly to the group in which she was allocated.

Also, time between the second and the third session was extended more than a month due to administrative reasons that caused a delay in placebo shipping.

Significant differences were also found in specific photodamage variables (Table 2).

Oozing, edema and vesiculation were not present in any group one week after each session (Table 3). Erythema and desquamation were significantly different in all sessions when both groups were compared, whereas pigmentation was statistically different only after the last session (Table 3).

Pain VAS scores after session 1 and 3 were not significantly different between the two groups, whereas they were found to be significantly different in session 2 (Table 4).

The majority of Skindex-29 scores showed non-statistical differences when baseline/after treatment scores were compared (p>0.05). However, individual scores of the MAL group in item 5 (My skin condition affects my social life) and item 14 (I tend to do things by myself because of my skin condition) showed statistical significant differences (p<0.05).

Overall, mean outside temperature during sessions was 28.60°C. All patients sun-exposed for 120min. Mean illuminance in each session varied from 82,478.75 through 72,528.56 and 70,419.1736lx (sessions 1, 2 and 3, respectively). Mean solar irradiance (W/m2) during the first, second and third sessions was 480.82, 430.07 and 435.84, respectively.

There was an imbalance between both groups in gender (more women than men) and just 1 patient in skin-phototype-I, it was not possible to evaluate effect interactions in these subgroups. However, when controlling only for skin phototype-II and III, a statistical significant association was found between the product received, and facial photodamage improvement (OR: 0.09; 95% CI: 0.01–0.81; p=0.03), whereas no statistical significant association was found between the intervention and the placebo group when irradiance was tested (OR: 1.00; 95% CI: 0.99–1.00; p=0.39). No association was found neither between age (OR: 1.05; 95% CI: 0.96–1.15; p=0.24) and treatment response, nor between facial photodamage improvement and time lapse between sessions (OR: 1.00; 95% CI: 0.95–1.05; p=0.92)

Also in the post hoc evaluation of subgroups interaction (excluding men and skin phototype-I), we did not find statistical significance of this relation (OR: 1.28; 95% CI: 0.23–7.17; p=0.77).

Two patients in the MAL group had serious events not related to the product. Another two patients (belonging to the MAL group) had non-serious adverse events which corresponded to a recurrence of herpes simplex related to sun-exposure (not previously reported by the patient) and a stressful situation. Another patient had a reaction to diacerein which was prescribed by her physician one week after the third session. Also, none of the patients in the placebo group presented with any AE.

The authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration.

The authors declare that they have followed the protocols of their work centre on the publication of patient data.

The authors must have obtained the informed consent of the patients and/or subjects mentioned in the article. The author for correspondence must be in possession of this document.