Light Dose Ranging Study of Photodynamic Therapy (PDT) With Levulan + Blue Light Versus Vehicle + Blue Light in Severe Facial Acne

• Change in Inflammatory Lesion Counts Relative to Baseline [ Time Frame: Baseline and 3 weeks after final treatment ] [ Designated as safety issue: No ]
• Investigator Global Assessment of Acne Severity Successes [ Time Frame: Baseline and 3 weeks after final treatment ] [ Designated as safety issue: No ]
  Scale consists of Grade 0 (clear skin) to Grade 4 (severe: up to many non-inflammatory and inflammatory lesions, but no more than a few nodular lesions) This assessment uses a dichotomized success/failure assessment - with success defined as a 2 point or more improvement on the IGA scale since baseline.

• Change in Lesion Counts relative to Baseline [ Time Frame: 3 weeks after final treatment ] [ Designated as safety issue: No ]
• Investigator Global Assessment (Using a Dichotomized Success/Failure Assessment - With Success Defined as a 2 Point or More Improvement on the IGA Scale) [ Time Frame: 3 weeks after final treatment ] [ Designated as safety issue: No ]

• Percent Change in Inflammatory Lesion Counts Relative to Baseline [ Time Frame: Baseline and 3 weeks after final treatment ] [ Designated as safety issue: No ]
• Percent Change in Inflammatory Lesion Counts Relative to Baseline [ Time Frame: Baseline and 6 weeks after final treatment ] [ Designated as safety issue: No ]
• Subject Satisfaction Score [ Time Frame: 6 weeks after final treatment ] [ Designated as safety issue: No ]

  Subject satisfaction score

  1. = Excellent (very satisfied)
  2. = Good (moderately satisfied)
  3. = Fair (slightly satisfied)
  4. = Poor (not satisfied at all)
• Change in Inflammatory Lesion Counts Relative to Baseline [ Time Frame: Baseline and 6 weeks after final treatment ] [ Designated as safety issue: No ]
  change in lesion counts compared to baseline
• Investigator Global Assessment of Acne Severity Successes [ Time Frame: Baesline and 6 weeks after final treatment ] [ Designated as safety issue: No ]

  Assessment uses a dichotomized success/failure assessment with success defined as a 2 point or more improvement since baseline.

  0 Clear skin with no inflam or non-inflam lesions

  1. Almost clear; rare non-inflam lesions with no more than a few small inflam lesions
  2. Mild; > Grade 1; some non-inflam lesions with some inflam lesions (papules/pustules only; no nodules)
  3. Moderate; > Grade 2; up to many non-inflam lesions and a moderate number of inflam lesions but no more than one small nodule
  4. Severe; > Grade 3; up to many non-inflam and inflam lesions, but no more than a few nodules
• Hyperpigmentation 48 Hours After PDT #1 [ Time Frame: 48 hours after PDT #1 ] [ Designated as safety issue: Yes ]
   HYPERPIGMENTATION SCALE Grade 0 = No hyperpigmentation Grade 1 = Light hyperpigmentation involving small areas Grade 2 = Moderate hyperpigmentation involving small areas; light hyperpigmentation involving moderate areas Grade 3 = Moderate hyperpigmentation involving moderate sized areas; light hyperpigmentation involving large areas; small areas of marked hyperpigmentation Grade 4 = Marked hyperpigmentation involving moderate or large sized areas
• Hyperpigmentation at Visit 3 (Week 3) [ Time Frame: Visit 3 (Week 3) ] [ Designated as safety issue: Yes ]
   HYPERPIGMENTATION SCALE Grade 0 = No hyperpigmentation Grade 1 = Light hyperpigmentation involving small areas Grade 2 = Moderate hyperpigmentation involving small areas; light hyperpigmentation involving moderate areas Grade 3 = Moderate hyperpigmentation involving moderate sized areas; light hyperpigmentation involving large areas; small areas of marked hyperpigmentation Grade 4 = Marked hyperpigmentation involving moderate or large sized areas
• Hyperpigmentation at Visit 5 (Week 6) [ Time Frame: Visit 5 (Week 6) ] [ Designated as safety issue: Yes ]
   HYPERPIGMENTATION SCALE Grade 0 = No hyperpigmentation Grade 1 = Light hyperpigmentation involving small areas Grade 2 = Moderate hyperpigmentation involving small areas; light hyperpigmentation involving moderate areas Grade 3 = Moderate hyperpigmentation involving moderate sized areas; light hyperpigmentation involving large areas; small areas of marked hyperpigmentation Grade 4 = Marked hyperpigmentation involving moderate or large sized areas
• Hyperpigmentation at Visit 7 (Week 9) [ Time Frame: Visit 7 (Week 9) ] [ Designated as safety issue: Yes ]
   HYPERPIGMENTATION SCALE Grade 0 = No hyperpigmentation Grade 1 = Light hyperpigmentation involving small areas Grade 2 = Moderate hyperpigmentation involving small areas; light hyperpigmentation involving moderate areas Grade 3 = Moderate hyperpigmentation involving moderate sized areas; light hyperpigmentation involving large areas; small areas of marked hyperpigmentation Grade 4 = Marked hyperpigmentation involving moderate or large sized areas
• Hyperpigmentation at Visit 9 (3 Weeks After Final PDT) [ Time Frame: Visit 9 (3 weeks after final PDT) ] [ Designated as safety issue: Yes ]
   HYPERPIGMENTATION SCALE Grade 0 = No hyperpigmentation Grade 1 = Light hyperpigmentation involving small areas Grade 2 = Moderate hyperpigmentation involving small areas; light hyperpigmentation involving moderate areas Grade 3 = Moderate hyperpigmentation involving moderate sized areas; light hyperpigmentation involving large areas; small areas of marked hyperpigmentation Grade 4 = Marked hyperpigmentation involving moderate or large sized areas
• Hyperpigmentation at Visit 10 (6 Weeks After Final PDT) [ Time Frame: Visit 10 (6 weeks after final PDT) ] [ Designated as safety issue: Yes ]
   HYPERPIGMENTATION SCALE Grade 0 = No hyperpigmentation Grade 1 = Light hyperpigmentation involving small areas Grade 2 = Moderate hyperpigmentation involving small areas; light hyperpigmentation involving moderate areas Grade 3 = Moderate hyperpigmentation involving moderate sized areas; light hyperpigmentation involving large areas; small areas of marked hyperpigmentation Grade 4 = Marked hyperpigmentation involving moderate or large sized areas
• Hypopigmentation 48 Hours Post PDT #1 [ Time Frame: 48 hours post PDT #1 ] [ Designated as safety issue: Yes ]
   HYPOPIGMENTATION SCALE Grade 0 = No hypopigmentation Grade 1 = Light hypopigmentation involving small areas Grade 2 = Moderate hypopigmentation involving small areas; light hypopigmentation involving moderate areas Grade 3 = Moderate hypopigmentation involving moderate sized areas; light hypopigmentation involving large areas; small areas of marked hypopigmentation Grade 4 = Marked hypopigmentation involving moderate or large sized areas
• Hypopigmentation at Visit 3 (Week 3) [ Time Frame: Visit 3 (Week 3) ] [ Designated as safety issue: Yes ]
   HYPOPIGMENTATION SCALE Grade 0 = No hypopigmentation Grade 1 = Light hypopigmentation involving small areas Grade 2 = Moderate hypopigmentation involving small areas; light hypopigmentation involving moderate areas Grade 3 = Moderate hypopigmentation involving moderate sized areas; light hypopigmentation involving large areas; small areas of marked hypopigmentation Grade 4 = Marked hypopigmentation involving moderate or large sized areas
• Hypopigmentation at Visit 5 (Week 6) [ Time Frame: Visit 5 (Week 6) ] [ Designated as safety issue: Yes ]
   HYPOPIGMENTATION SCALE Grade 0 = No hypopigmentation Grade 1 = Light hypopigmentation involving small areas Grade 2 = Moderate hypopigmentation involving small areas; light hypopigmentation involving moderate areas Grade 3 = Moderate hypopigmentation involving moderate sized areas; light hypopigmentation involving large areas; small areas of marked hypopigmentation Grade 4 = Marked hypopigmentation involving moderate or large sized areas
• Hypopigmentation at Visit 7 (Week 9) [ Time Frame: Visit 7 (Week 9) ] [ Designated as safety issue: Yes ]
   HYPOPIGMENTATION SCALE Grade 0 = No hypopigmentation Grade 1 = Light hypopigmentation involving small areas Grade 2 = Moderate hypopigmentation involving small areas; light hypopigmentation involving moderate areas Grade 3 = Moderate hypopigmentation involving moderate sized areas; light hypopigmentation involving large areas; small areas of marked hypopigmentation Grade 4 = Marked hypopigmentation involving moderate or large sized areas
• Hypopigmentation at Visit 9 (3 Weeks After Final PDT) [ Time Frame: Visit 9 (3 weeks after final PDT) ] [ Designated as safety issue: Yes ]
   HYPOPIGMENTATION SCALE Grade 0 = No hypopigmentation Grade 1 = Light hypopigmentation involving small areas Grade 2 = Moderate hypopigmentation involving small areas; light hypopigmentation involving moderate areas Grade 3 = Moderate hypopigmentation involving moderate sized areas; light hypopigmentation involving large areas; small areas of marked hypopigmentation Grade 4 = Marked hypopigmentation involving moderate or large sized areas
• Hypopigmentation at Visit 10 (6 Weeks After Final PDT) [ Time Frame: Visit 10 (6 weeks after final PDT) ] [ Designated as safety issue: Yes ]
   HYPOPIGMENTATION SCALE Grade 0 = No hypopigmentation Grade 1 = Light hypopigmentation involving small areas Grade 2 = Moderate hypopigmentation involving small areas; light hypopigmentation involving moderate areas Grade 3 = Moderate hypopigmentation involving moderate sized areas; light hypopigmentation involving large areas; small areas of marked hypopigmentation Grade 4 = Marked hypopigmentation involving moderate or large sized areas
• Erythema at Baseline (Pre-light) [ Time Frame: Baseline (pre-light) ] [ Designated as safety issue: Yes ]

  After solution application, prior to light treatment

   Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema

• Erythema at Baseline - Post Light Treatment [ Time Frame: Baseline - post light treatment ] [ Designated as safety issue: Yes ]
  Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema
• Erythema 48 Hours After PDT #1 [ Time Frame: 48 hours after PDT #1 ] [ Designated as safety issue: Yes ]
  Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema
• Erythema at Visit 3 (Week 3 - Pre Study Drug Application) [ Time Frame: Visit 3 (Week 3 - pre study drug application) ] [ Designated as safety issue: Yes ]
  Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema
• Erythema at Visit 3 (Week 3 - Pre-light) [ Time Frame: Visit 3 (Week 3 - pre-light) ] [ Designated as safety issue: Yes ]
  Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema
• Erythema at Visit 3 (Week 3 - Post Light Treatment) [ Time Frame: Visit 3 (Week 3 - post light treatment) ] [ Designated as safety issue: Yes ]
  Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema
• Erythema at Visit 5 (Week 6 - Prior to Study Drug Application) [ Time Frame: Visit 5 (Week 6 - prior to study drug application) ] [ Designated as safety issue: Yes ]
  Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema
• Erythema at Visit 5 (Weeks 6 - Pre-light Treatment) [ Time Frame: Visit 5 (Weeks 6 - pre-light treatment) ] [ Designated as safety issue: Yes ]
  Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema
• Erythema at Visit 5 (Week 6 - Post Light Treatment) [ Time Frame: Visit 5 (Week 6 - post light treatment) ] [ Designated as safety issue: Yes ]
  Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema
• Erythema at Visit 7 (Week 9 - Prior to Study Drug Application) [ Time Frame: Visit 7 (Week 9 - prior to study drug application) ] [ Designated as safety issue: Yes ]
  Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema
• Erythema at Visit 7 (Week 9 - Pre Light Treatment) [ Time Frame: Visit 7 (Week 9 - pre light treatment) ] [ Designated as safety issue: Yes ]
  Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema
• Erythema at Visit 7 (Week 9 - Post Light Treatment) [ Time Frame: Visit 7 (Week 9 - post light treatment) ] [ Designated as safety issue: Yes ]
  Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema
• Erythema 3 Weeks After Final PDT [ Time Frame: 3 Weeks after Final PDT ] [ Designated as safety issue: Yes ]
  Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema
• Erythema 6 Weeks After Final PDT [ Time Frame: 6 Weeks after Final PDT ] [ Designated as safety issue: Yes ]
  Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema
• Edema at Baseline - Pre Light Treatment [ Time Frame: Baseline - pre light treatment ] [ Designated as safety issue: Yes ]
  EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area
• Edema at Baseline - Post Light Treatment [ Time Frame: Baseline - Post Light Treatment ] [ Designated as safety issue: Yes ]
  EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area
• Edema 48 Hours After PDT #1 [ Time Frame: 48 hours after PDT #1 ] [ Designated as safety issue: Yes ]
  EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area
• Edema at Visit 3 (Week 3 - Before Study Drug Application) [ Time Frame: Visit 3 (Week 3 - before study drug application) ] [ Designated as safety issue: Yes ]
  EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area
• Edema at Visit 3 (Week 3 - Before Light Treatment) [ Time Frame: Visit 3 (Week 3 - before light treatment) ] [ Designated as safety issue: Yes ]
  EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area
• Edema at Visit 3 (Week 3 - Post Light Treatment) [ Time Frame: Visit 3 (Week 3 - post light treatment) ] [ Designated as safety issue: Yes ]
  EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area
• Edema at Visit 5 (Week 6 - Before Study Drug Application) [ Time Frame: Visit 5 (Week 6 - before study drug application) ] [ Designated as safety issue: Yes ]
  EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area
• Edema at Visit 5 (Week 6 - Pre Light Treatment) [ Time Frame: Visit 5 (Week 6 - pre light treatment) ] [ Designated as safety issue: Yes ]
  EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area
• Edema at Visit 5 (Week 6 - Post Light Treatment) [ Time Frame: Visit 5 (Week 6 - post light treatment) ] [ Designated as safety issue: Yes ]
  EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area
• Edema at Visit 7 (Week 9 - Before Study Drug Application) [ Time Frame: Visit 7 (Week 9 - before study drug application) ] [ Designated as safety issue: Yes ]
  EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area
• Edema at Visit 7 (Week 9 - Prior to Light Treatment) [ Time Frame: Visit 7 (Week 9 - prior to light treatment) ] [ Designated as safety issue: Yes ]
  EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area
• Edema at Visit 7 (Week 9 - Post Light Treatment) [ Time Frame: Visit 7 (Week 9 - post light treatment) ] [ Designated as safety issue: Yes ]
  EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area
• Edema 3 Weeks After Final PDT [ Time Frame: 3 weeks after final PDT ] [ Designated as safety issue: Yes ]
  EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area
• Edema 6 Weeks After Final PDT [ Time Frame: 6 weeks after final PDT ] [ Designated as safety issue: Yes ]
  EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area
• Stinging/Burning at Baseline - Before Light Treatment [ Time Frame: Baseline - before light treatment ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Baseline - During Light [ Time Frame: Baseline - during light ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Baseline - Post Light Treatment [ Time Frame: Baseline - post light treatment ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning 48 Hours Post PDT #1 [ Time Frame: 48 hours post PDT #1 ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Visit 3 (Week 3 - Before Study Drug Application) [ Time Frame: Visit 3 (Week 3 - before study drug application) ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Visit 3 (Week 3 - Before Light Treatment) [ Time Frame: Visit 3 (Week 3 - before light treatment) ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Visit 3 (Week 3 - During Light Treatment) [ Time Frame: Visit 3 (Week 3 - during light treatment) ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Visit 3 (Week 3 - Post Light Treatment) [ Time Frame: Visit 3 (Week 3 - post light treatment) ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Visit 5 (Week 6 - Before Study Drug Application) [ Time Frame: Visit 5 (Week 6 - before study drug application) ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Visit 5 (Week 6 - Prior to Light Treatment) [ Time Frame: Visit 5 (Week 6 - prior to light treatment) ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Visit 5 (Week 6 - During Light Treatment) [ Time Frame: Visit 5 (Week 6 - during light treatment) ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Visit 5 (Week 6 - Post Light Treatment) [ Time Frame: Visit 5 (Week 6 - post light treatment) ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Visit 7 (Week 9 - Before Study Drug Application) [ Time Frame: Visit 7 (Week 9 - before study drug application) ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Visit 7 (Week 9 - Prior to Light Treatment) [ Time Frame: Visit 7 (Week 9 - prior to light treatment) ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Visit 7 (Week 9 - During Light Treatment) [ Time Frame: Visit 7 (Week 9 - during light treatment) ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Visit 7 (Week 9 - Post Light Treatment) [ Time Frame: Visit 7 (Week 9 - post light treatment) ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Visit 9 (3 Weeks After Final PDT) [ Time Frame: Visit 9 (3 Weeks after Final PDT) ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Stinging/Burning at Visit 10 (6 Weeks After Final PDT) [ Time Frame: Visit 10 (6 Weeks after Final PDT) ] [ Designated as safety issue: Yes ]
  STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable
• Scaling and Dryness 48 Hours After PDT #1 [ Time Frame: 48 hours after PDT #1 ] [ Designated as safety issue: Yes ]
  SCALING AND DRYNESS SCALE Grade 0 = None Grade 1 = Minimal - barely perceptible desquamation Grade 2 = Mild - limited areas of fine desquamation in up to 1/3 of the treatment area Grade 3 = Moderate - fine desquamation involving 1/3 to 2/3 of the treatment area or limited areas of coarser scaling Grade 4 = Severe - coarser scaling involving more than 2/3 of the treatment area or limited areas of very coarse scaling
• Scaling and Dryness at Visit 3 (Week 3) [ Time Frame: Visit 3 (Week 3) ] [ Designated as safety issue: Yes ]
  SCALING AND DRYNESS SCALE Grade 0 = None Grade 1 = Minimal - barely perceptible desquamation Grade 2 = Mild - limited areas of fine desquamation in up to 1/3 of the treatment area Grade 3 = Moderate - fine desquamation involving 1/3 to 2/3 of the treatment area or limited areas of coarser scaling Grade 4 = Severe - coarser scaling involving more than 2/3 of the treatment area or limited areas of very coarse scaling
• Scaling and Dryness at Visit 5 (Week 6) [ Time Frame: Visit 5 (Week 6) ] [ Designated as safety issue: Yes ]
  SCALING AND DRYNESS SCALE Grade 0 = None Grade 1 = Minimal - barely perceptible desquamation Grade 2 = Mild - limited areas of fine desquamation in up to 1/3 of the treatment area Grade 3 = Moderate - fine desquamation involving 1/3 to 2/3 of the treatment area or limited areas of coarser scaling Grade 4 = Severe - coarser scaling involving more than 2/3 of the treatment area or limited areas of very coarse scaling
• Scaling and Dryness at Visit 7 (Week 9) [ Time Frame: Visit 7 (Week 9) ] [ Designated as safety issue: Yes ]
  SCALING AND DRYNESS SCALE Grade 0 = None Grade 1 = Minimal - barely perceptible desquamation Grade 2 = Mild - limited areas of fine desquamation in up to 1/3 of the treatment area Grade 3 = Moderate - fine desquamation involving 1/3 to 2/3 of the treatment area or limited areas of coarser scaling Grade 4 = Severe - coarser scaling involving more than 2/3 of the treatment area or limited areas of very coarse scaling
• Scaling and Dryness at Visit 9 (3 Weeks After Final PDT) [ Time Frame: Visit 9 (3 Weeks after Final PDT) ] [ Designated as safety issue: Yes ]
  SCALING AND DRYNESS SCALE Grade 0 = None Grade 1 = Minimal - barely perceptible desquamation Grade 2 = Mild - limited areas of fine desquamation in up to 1/3 of the treatment area Grade 3 = Moderate - fine desquamation involving 1/3 to 2/3 of the treatment area or limited areas of coarser scaling Grade 4 = Severe - coarser scaling involving more than 2/3 of the treatment area or limited areas of very coarse scaling
• Scaling and Dryness at Visit 10 (6 Weeks After Final PDT) [ Time Frame: Visit 10 (6 Weeks after Final PDT) ] [ Designated as safety issue: Yes ]
  SCALING AND DRYNESS SCALE Grade 0 = None Grade 1 = Minimal - barely perceptible desquamation Grade 2 = Mild - limited areas of fine desquamation in up to 1/3 of the treatment area Grade 3 = Moderate - fine desquamation involving 1/3 to 2/3 of the treatment area or limited areas of coarser scaling Grade 4 = Severe - coarser scaling involving more than 2/3 of the treatment area or limited areas of very coarse scaling
• Oozing/Vesiculation/Crusting 48 Hours After PDT #1 [ Time Frame: 48 hours after PDT #1 ] [ Designated as safety issue: Yes ]
  OOZING/VESICULATION/CRUSTING Grade 0 = None Grade 1 = Minimal - a single area of oozing, vesiculation or crusting 3 mm diameter or less in size Grade 2 = Mild - two to four areas of oozing, vesiculation or crusting 3 mm diameter or less in size OR a single area larger than 3 mm diameter in size Grade 3 = Moderate - more than a single area of oozing, vesiculation or crusting larger than 3 mm diameter in size or more than four areas of 3 mm diameter or less in size Grade 4 = Severe - any degree of oozing, vesiculation or crusting greater than (3) above
• Oozing/Vesiculation/Crusting at Visit 3 (Week 3) [ Time Frame: Visit 3 (Week 3) ] [ Designated as safety issue: Yes ]
  OOZING/VESICULATION/CRUSTING Grade 0 = None Grade 1 = Minimal - a single area of oozing, vesiculation or crusting 3 mm diameter or less in size Grade 2 = Mild - two to four areas of oozing, vesiculation or crusting 3 mm diameter or less in size OR a single area larger than 3 mm diameter in size Grade 3 = Moderate - more than a single area of oozing, vesiculation or crusting larger than 3 mm diameter in size or more than four areas of 3 mm diameter or less in size Grade 4 = Severe - any degree of oozing, vesiculation or crusting greater than (3) above
• Oozing/Vesiculation/Crusting at Visit 5 (Week 6) [ Time Frame: Visit 5 (Week 6) ] [ Designated as safety issue: Yes ]
  OOZING/VESICULATION/CRUSTING Grade 0 = None Grade 1 = Minimal - a single area of oozing, vesiculation or crusting 3 mm diameter or less in size Grade 2 = Mild - two to four areas of oozing, vesiculation or crusting 3 mm diameter or less in size OR a single area larger than 3 mm diameter in size Grade 3 = Moderate - more than a single area of oozing, vesiculation or crusting larger than 3 mm diameter in size or more than four areas of 3 mm diameter or less in size Grade 4 = Severe - any degree of oozing, vesiculation or crusting greater than (3) above
• Oozing/Vesiculation/Crusting at Visit 7 (Week 9) [ Time Frame: Visit 7 (Week 9) ] [ Designated as safety issue: Yes ]
  OOZING/VESICULATION/CRUSTING Grade 0 = None Grade 1 = Minimal - a single area of oozing, vesiculation or crusting 3 mm diameter or less in size Grade 2 = Mild - two to four areas of oozing, vesiculation or crusting 3 mm diameter or less in size OR a single area larger than 3 mm diameter in size Grade 3 = Moderate - more than a single area of oozing, vesiculation or crusting larger than 3 mm diameter in size or more than four areas of 3 mm diameter or less in size Grade 4 = Severe - any degree of oozing, vesiculation or crusting greater than (3) above
• Oozing/Vesiculation/Crusting at Visit 9 (3 Weeks After Final PDT) [ Time Frame: Visit 9 (3 Weeks after Final PDT) ] [ Designated as safety issue: Yes ]
  OOZING/VESICULATION/CRUSTING Grade 0 = None Grade 1 = Minimal - a single area of oozing, vesiculation or crusting 3 mm diameter or less in size Grade 2 = Mild - two to four areas of oozing, vesiculation or crusting 3 mm diameter or less in size OR a single area larger than 3 mm diameter in size Grade 3 = Moderate - more than a single area of oozing, vesiculation or crusting larger than 3 mm diameter in size or more than four areas of 3 mm diameter or less in size Grade 4 = Severe - any degree of oozing, vesiculation or crusting greater than (3) above
• Oozing/Vesiculation/Crusting at Visit 10 (6 Weeks After Final PDT) [ Time Frame: Visit 10 (6 Weeks after Final PDT) ] [ Designated as safety issue: Yes ]
  OOZING/VESICULATION/CRUSTING Grade 0 = None Grade 1 = Minimal - a single area of oozing, vesiculation or crusting 3 mm diameter or less in size Grade 2 = Mild - two to four areas of oozing, vesiculation or crusting 3 mm diameter or less in size OR a single area larger than 3 mm diameter in size Grade 3 = Moderate - more than a single area of oozing, vesiculation or crusting larger than 3 mm diameter in size or more than four areas of 3 mm diameter or less in size Grade 4 = Severe - any degree of oozing, vesiculation or crusting greater than (3) above

• Percent Change in Lesion Counts [ Time Frame: 3 and 6 weeks after final treatment ] [ Designated as safety issue: No ]
• Subject Acceptability of Treatment [ Time Frame: 3 and 6 weeks after final treatment ] [ Designated as safety issue: No ]
• Change in Lesion Counts and IGA [ Time Frame: 6 weeks after final treatment ] [ Designated as safety issue: No ]
• Tolerability Parameters [ Time Frame: Each Visit ] [ Designated as safety issue: Yes ]

The purpose of this study is to determine and compare the safety and efficacy of multiple broad area photodynamic therapy treatments with aminolevulinic acid (ALA-PDT) and vehicle (VEH-PDT) in subjects with moderate to severe facial acne vulgaris.

This is a Phase II multicenter, randomized, evaluator-blinded, vehicle-controlled, parallel group light dose ranging study of photodynamic therapy in subjects with moderate to severe facial acne vulgaris.

Subjects will be randomized to one of the following four treatment groups (1:1:1:1) to receive topical Levulan® Kerastick® containing 20% aminolevulinic acid HCL (ALA, active study drug) or the Kerastick® containing vehicle ingredients only (VEH).

• Group 1 will have ALA applied to the entire facial area 45 minutes ± 15 minutes prior to BLUE light treatment for 1000 seconds (16 minutes 40 seconds)
• Group 2 will have ALA applied to the entire facial area 45 minutes ± 15 minutes prior to BLUE light treatment for 500 seconds (8 minutes 20 seconds)
• Group 3 will have VEH applied to the entire facial area 45 minutes ± 15 minutes prior to BLUE light treatment for 1000 seconds (16 minutes 40 seconds)
• Group 4 will have VEH applied to the entire facial area 45 minutes ± 15 minutes prior to BLUE light treatment for 500 seconds (8 minutes 20 seconds)

Each subject may receive up to four treatments at three week (± 2 days) intervals. The power density (dose rate) and the total fluence (light dose) used at each treatment is intended to remain constant throughout each subject's participation. If a subject meets or exceeds the criteria restricting retreatment (CRR) prior to retreatment (Section 5.6), he/she will not receive additional PDT treatment at that visit and will be asked to return for the next scheduled PDT visit 3 weeks later, if applicable.

Post-treatment follow-up visits will be scheduled to occur at 3 and 6 weeks after the subject's final PDT.

Grading of the subject's facial acne will be conducted by a blinded evaluator who will remain blinded with respect to the subject's treatment assignment. Tolerability of treatment will be assessed by evaluations of the local skin response (erythema, edema, etc.) and will be conducted by an unblinded evaluator.

Safety will be evaluated by adverse events and local skin responses reported during the study.

• Drug: aminolevulinic acid HCL (ALA)
  Levulan Kerastick containing 20% aminolevulinic acid HCL (ALA). Up to 4 treatments will be given at 3 week intervals.
  Other Names:

  • Levulan
  • Levulan Kerastick
• Other: Vehicle (VEH)
  Levulan Kerastick containing vehicle ingredients only (VEH). Up to 4 treatments will be given at 3 week intervals.

• Active Comparator: ALA 1000 seconds
  Aminolevulinic acid HCL (ALA) applied to the entire facial area 45 minutes prior to BLUE light treatment for 1000 seconds (16 minutes and 40 seconds)
  Intervention: Drug: aminolevulinic acid HCL (ALA)
• Active Comparator: ALA 500 seconds
  Aminolevulinic acid HCL (ALA) applied to the entire facial area 45 minutes prior to BLUE light treatment for 500 seconds (8 minutes and 20 seconds)
  Intervention: Drug: aminolevulinic acid HCL (ALA)
• Placebo Comparator: Vehicle 1000 seconds
  Vehicle (VEH) applied to the entire facial area 45 minutes prior to BLUE light treatment for 1000 seconds (16 minutes and 40 seconds)
  Intervention: Other: Vehicle (VEH)
• Placebo Comparator: Vehicle 500 seconds
  Vehicle (VEH) applied to the entire facial area 45 minutes prior to BLUE light treatment for 500 seconds (8 minutes 20 seconds)
  Intervention: Other: Vehicle (VEH)

Inclusion Criteria:

• Subject is male or non-pregnant female 12 years of age or older.
• Females must be post-menopausal, surgically sterile or using a medically acceptable form of birth control, with a negative urine pregnancy test at the Baseline visit.
• Subject has provided written and verbal informed consent. A subject under 18 years of age must be accompanied by the parent or legal guardian at the time of assent/consent signing. The parent or legal guardian must also provide informed consent for the subject.
• Subject has moderate to severe facial acne vulgaris (including the nose), with at least 20 inflammatory lesions (papules, pustules, nodules).
• Subject has moderate to severe acne as defined by an Investigator Global Assessment of 3 or 4 [0 (clear) to 4 (severe) scale].
• Subject has a history of recurrent herpes simplex labialis infection in the treatment area AND has had an outbreak within the last 12 months must be placed on antiviral prophylaxis as specified in the protocol.
• Subject is willing to comply with study instructions and return to the clinic for required visits.
• Subject must have used the same type and brand of make-up, other facial products and hair products (e.g. shampoo, gel, hair spray, mousse, etc.) for at least 1 month prior to the Baseline Visit (General Skin & Hair Care). Upon enrollment, all subjects must a) use exclusively an Investigator approved facial cleanser and b) agree to continue their other General Skin & Hair Care for the entire study.

Exclusion Criteria:

• Subject is pregnant, lactating, or is planning to become pregnant during the study.
• Subject has a history of cutaneous photosensitization, porphyria, hypersensitivity to porphyrins or photodermatosis.
• Subject has any skin pathology or condition that could interfere with the evaluation of the test product or requires the use of interfering topical or systemic therapy.
• Subject has greater than 4 facial nodules (nodule = lesion greater than or equal 0.5 cm in diameter)
• Subject has an uncorrected coagulation defect or concurrently uses anticoagulants (except aspirin).
• Subject has any condition which, in the investigator's opinion, would make it unsafe for the subject to participate in this research study.
• Subject is currently enrolled in an investigational drug or device study.
• Subject has received an investigational drug or been treated with an investigational device within 30 days prior to the initiation of treatment (baseline).
• Subject has facial hair that could interfere with the study assessments in the opinion of the investigator.
• Subject is unable to communicate or cooperate with the investigator due to language problems, poor mental development, or impaired cerebral function.
• Subject may be unreliable for the study including subjects who engage in excessive alcohol intake or drug abuse, or subjects who are unable to return for scheduled follow-up visits.
• Subject has a known sensitivity to one or more of the vehicle components (ethyl alcohol, isopropyl alcohol, laureth 4, polyethylene glycol).
• Subject has used photosensitizing drugs, e.g. declomycin, tetracycline, sulfa antibiotics, phenothiazines, etc. within a timeframe where photosensitization from these drugs may still be present.
• Subject has used OTC acne medicated cleansers or soaps within 2 weeks of the initiation of treatment.
• Subject has the need or plans to be exposed to artificial tanning devices or excessive sunlight during the trial.
• Subject has used any of the following topical anti-acne preparations on the face: a.) Topical anti-acne treatments including benzoyl peroxide, antibiotics, azelaic acid, corticosteroids and salicylic acid within 2 weeks of the initiation of treatment b.) Retinoids, including tazarotene, adapalene, tretinoin within 4 weeks of the initiation of treatment. c.) Light treatments, microdermabrasion or chemical peels within 8 weeks of the initiation of treatment.
• Subject has used any of the following systemic anti-acne medications: a.) Corticosteroids (including intramuscular and intralesional injections) within 4 weeks of the initiation of treatment. Inhaled corticosteroids are allowed if use is stable (stable use is defined as dose and frequency unchanged for at least 2 weeks prior to the initiation of treatment). b.) Antibiotics within 4 weeks of the initiation of treatment. c.) Nicotinamide containing products within 4 weeks of the initiation of treatment. d.) Spironolactone within 8 weeks of the initiation of treatment. d.) Retinoid therapy within 6 months of the initiation of treatment.