PHASE II CLINICAL TRIAL USING OCTADECENEDIOIC ACID AND BENZOYL PEROXIDE

15 May

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

12 weeks;

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

Propionibacteria.

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.

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