Although research into improving the delivery of DCA via formulation design was still ongoing, it was decided to extend the clinical investigation by examining the antibacterial activity of DCA in patients with mild-to-moderate acne, instead of healthy human volunteers, and to extend the time of the investigation to
12 weeks instead of three. As the improved delivery systems of DCA were not yet available, we continued with the DCA-containing gel formulation in this Phase II clinical trial. The objectives of the second clinical study were as follows:
1. to investigate whether the antibacterial effects of DCA against P. acnes, when applied to the skin of healthy volunteers over three weeks, could be reproduced when DCA was applied to the skin of patients with mild-to-moderate acne over
2. to determine whether DCA demonstrated any clinical efficacy when applied to the skin of patients with mild-to-moderate acne;
3. to determine the tolerability of DCA on the skin of the patients.
Four formulations were tested in a randomized, double-blind, placebo, and active- treatment controlled trial using 60 volunteers with mild-to-moderate acne vulgaris and a clinically significant level of skin surface P. acnes. As in the first trial, the volun- teers were medically screened to ensure their suitability to undertake the study. Their willingness to participate was documented through completion of an informed consent form in the presence of medical staff. Patients were stratified according to the number of P. acnes isolated from their skin at the screening visit and randomized to receive one of the following treatments: (i) DCA (10%) in an aqueous gel; (ii) DCA (2%) in an aqueous gel; (iii) aqueous gel without any active ingredient, the vehicle; or (iv) 5% BPO (Panoxyl Aquagel 5). The latter formulation was selected as the active treatment control because it is recognized as a safe, effective, nonantibiotic, and anti- bacterial agent and treatment for acne. Topical applications were made twice daily to the face.
Clinical grading and microbiological count was done at weeks 0, 2, 4, 6, and
12, and adverse events and product tolerability and perceptions were measured at weeks 2, 4, 6, and 12. The primary efficacy variables evaluated were the change in the number of total acne lesions from baseline and the change in the number of surface P. acnes from baseline. Secondary efficacy variables included the change in the number of inflamed and noninflamed acne lesions from baseline and the change in the acne grade from baseline. More details on the methodology can be found in the literature (20).
Sixty patients were recruited into the study, with 15 patients in each treatment group. Fifty-two patients completed the study without major protocol violations.
FIGURE 8 The change in total lesion count from baseline following a 12-week treatment with the aqueous vehicle [0% octadecenedioic acid (0% DCA)], the same aqueous vehicle containing 2% DCA, the same aqueous vehicle containing 10% DCA or 5% benzoyl peroxide (Panoxyl Aquagel
5). Products were applied twice daily to the face. Abbreviations: BPO, benzoyl peroxide; DCA, octadecenedioic acid.
Five patients withdrew due to acne exacerbation and three were lost during follow- up. The results from this second study were as follows:
1. There was a significant reduction in total acne lesions in subjects using 10% DCA (P ,0.05) and 5% BPO (P ,0.001) after 12 weeks (Fig. 8).
2. There was a significant reduction in the number of inflamed lesions in subjects using 10% DCA (P ,0.05), 2% DCA (P ,0.05), and 5% BPO (P ,0.01) after
12 weeks. There was a significant reduction in the number of noninflamed lesions in subjects using 5% BPO (P ,0.05) at week 12.
3. BPO at 5% significantly reduced P. acnes at weeks 2, 4, 6, and 12 (P ,0.001).
4. DCA at 10% significantly reduced the number of Micrococcaceae at weeks
2, 4, and 6 (P ,0.05) but did not significantly reduce the number of
5. Seventy-three percent of patients treated with 5% BPO and 53% of patients treated with 10% DCA had a decrease in overall acne grade at week 12.
6. Both DCA treatments were very well tolerated on the skin when compared with
5% BPO and the vehicle (Table 3).
It could therefore be concluded that DCA demonstrated a significant clinical effect against acne, as measured by the most reliable assessment method available, i.e., lesion counting. The reduction in acne lesions, in particular inflamed lesions, was not reflected by a concomitant reduction in the number of P. acnes on the subjects’ skin. DCA compared favorably to 5% BPO in its ability to reduce acne lesions (Fig. 8) and also its tolerance profile (Table 3). The reduced antibacterial activity of DCA compared with the phase I study and the in vitro results listed in Table 1
TABLE 3 Percentage of Patients in Each Treatment Group Who Experienced Tolerance-Related Adverse Reactions Following a Twice Daily Application of the Aqueous Vehicle (Gel Vehicle), the Same Aqueous Vehicle Containing 2% Octadecenedioic Acid (2% DCA), the Same Aqueous Vehicle Containing 10% DCA, or 5% Benzoyl Peroxide (Panoxyl Aquagel 5)
may be due to the inability of the formulation to persist on the skin and penetrate into the follicles at sufficiently high levels to exert its activity. In the meantime, new formulations have been made that deliver significantly more DCA to the skin at much lower concentrations of DCA (2%) (21), and it is expected that these new formulations will be more efficacious.