A Phase 2a Study to Evaluate the Safety and Efficacy of AZX100 in Trocar Sites of Arthroscopic Shoulder Surgery Patients

• Placebo (Drug): Patients in the Placebo-only arm were dosed intradermally with placebo (saline) in three trocar sites on Day 9 (plus/minus 2 days) and Day 21 (plus/minus 2 days) after arthroscopic shoulder surgery. In the AZX100-placebo arm, 3 or 10 mg or placebo (saline) was administered intradermally at each of three trocar sites on each patient 9 ± 2 days and 21 ± 2 days after arthroscopic surgery. The three trocar sites (anterior, lateral, and posterior sides of the shoulder) were randomized to receive the same dose of study agent for both dose administrations.
• AZX100 (Drug): AZX100 Drug Product 3 or 10 mg or placebo (saline) was administered intradermally at each of three trocar sites on each patient 9 ± 2 days and 21 ± 2 days after arthroscopic surgery. The three trocar sites (anterior, lateral, and posterior sides of the shoulder) were randomized to receive the same dose of study agent for both dose administrations.

Primary outcomes

• Differences Among the 3 Dosage Groups in the Patient (PSAS) and Observer (OSAS) Scar Assessment Scale (POSAS) Scores [12 months]: Efficacy was based on the difference between mean POSAS scores of placebo and 3 mg AZX100, and placebo and 10 mg AZX100 12 months after shoulder surgery. Three trocar sites were randomized on each patient to receive AZX100 3 mg or AZX100 10 mg or placebo at 9 days and 21 days after shoulder surgery. PSAS results included patients' ratings on a scale of 1-10 (1 was normal skin or no complaints and 10 was the worst imaginable scar or the worst difference) for the following: Is the scar painful? Is the scar itching? Is the color of the scar different? Is the scar more stiff? Is the thickness of the scar different? Is the scar irregular? The possible minimum score was 6 and the maximum (worst) score was 60. OSAS results included observers' ratings on a scale of 1-10 (1 was normal skin and 10 was the worst scar imaginable) for vascularization, pigmentation, thickness, relief, and pliability. The possible minimum score was 5 and the possible maximum (worst) score was 50.

Secondary outcomes

• Between-group Mean Differences in Visual Analog Scale Scores Rated by Independent Blinded Raters Using 3D Photography [12 months]: Three trocar sites were randomized on each patient to receive AZX100 3 mg/cm or AZX100 10 mg/cm or saline placebo/cm at 9 days and 21 days after surgery. Twelve months after surgery, images of the trocar sites were longitudinally evaluated and rated using a standard 100 mm Visual Analog Scale (VAS) by two blinded independent dermatologists, with 0 being normal skin and 100 being the worst scar imaginable. Efficacy was based on the difference between VAS scores of placebo and 3 mg AZX100 and placebo and 10 mg AZX100 for each of the two raters separately. Data from both raters was not combined.
• Between-group Mean Differences in Objective Measures Via 3D Photography (Elevation, Length, Width) [12 months]: Three trocar sites designated as anterior, lateral and posterior were randomized on each patient to receive AZX100 3 mg/cm or AZX100 10 mg/cm or placebo/cm at 9 days and 21 days following shoulder surgery. 3D digital photography of each trocar scar was used to calculate scar length, width, minimum elevation, and maximum elevation in millimeters (mm) at 12 months. The minimum elevation value was calculated as the lowest point of the scar below the interpolated smooth skin surface. This was always a negative number. Negative values (closer to zero) were more desirable. The maximum elevation value was the highest point of the scar above the interpolated smooth skin surface. A smaller value was preferred.
• Between-group Mean Differences in Objective Measures Via 3D Photography (Volume) [12 months]: Three trocar sites designated as anterior, lateral and posterior were randomized on each patient to receive AZX100 3 mg/cm, or AZX100 10 mg/cm, or placebo/cm at 9 days and 21 days following shoulder surgery. 3D digital photography of each trocar scar was used to calculate positive volume, negative volume, and total volume in millimeters cubed (mm\^3) at 12 months. Positive volume included the scar volume that was calculated to be above the interpolated smooth skin surface. A smaller value was preferred. Negative volume included the volume of the scar calculated to be below the interpolated smooth skin surface. It was always a negative number; negative values (closer to zero) were more desirable. Total volume was calculated as the sum of positive volume and the absolute value of negative volume. Smaller values were more desirable.
• Histological Evaluation of Collagen [12 months]: Three trocar sites designated as anterior, lateral and posterior were randomized on each patient to receive AZX100 3 mg/cm or AZX100 10 mg/cm or placebo/cm at 9 days and 21 days following shoulder surgery. A skin punch biopsy was taken of each trocar site at 12 months. The specimens were blindly scored in duplicate by a dermal pathologist for dermal collagen fiber density, maturity and orientation, where 0% was completely normal and 100% was completely abnormal.
• Histological Evaluation of Number of Alpha Smooth Muscle Actin Cells [12 months]: Three trocar sites designated as anterior, lateral and posterior were randomized on each patient to receive AZX100 3 mg/cm or AZX100 10 mg/cm or placebo/cm at 9 days and 21 days following shoulder surgery. A skin punch biopsy was taken of each trocar site at 12 months. For exploratory purposes, the specimens were blindly scored in duplicate by a dermal pathologist for the estimated number of alpha-smooth muscle actin (α-SMA) positive cells per high powered field. Values ranged from 0 to several hundred. The number of α-SMA cells was assessed for exploratory purposes; therefore, at the time of this report, it was not known whether it was better to have a low or high α-SMA score.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* Scheduled for an arthroscopic shoulder surgery that will result in at least 3 trocar sites
* Healthy male or non-pregnant female 18-75 years old
* Non-diabetic
* Body Mass Index 18-35
* No clinically significant abnormal values on blood test
* Non-smoker for previous 6 months

Exclusion Criteria:

* History of acute or chronic disease
* Cancer within previous 5 years, except for removed skin cancer
* Hypersensitivity reaction
* Allergy to general anesthesia, lidocaine, or epinephrine
* Current skin disorder other than folliculitis or acne
* On therapy with steroids
* On therapy with a drug that affects collagen synthesis
* Positive for HIV or hepatitis
* Positive urine test for nicotine
* Positive blood test for anti-AZX100 antibodies
* Participated in another clinical study within 60 days before enrollment
* Gave blood within 7 days before dosing
* Gave plasma within 3 days before dosing
* Tattoo on the shoulder area
* Applied any prescribed or over the counter agents to the shoulder within 14 days before dosing, or intend to use any scar improving product
* Visited a tanning salon within 14 days before dosing
* History of drug addiction or excessive use of alcohol

Participant flow

Outcome results

• Differences Among the 3 Dosage Groups in the Patient (PSAS) and Observer (OSAS) Scar Assessment Scale (POSAS) Scores (Primary), Mean, Units on a scale: PSAS Results for Placebo Trocar Scars 8.0 +/- 4.1; PSAS Results for 3 mg AZX100 Trocar Scars 8.0 +/- 4.7; PSAS Results for 10 mg AZX100 Trocar Scars 8.3 +/- 5.0; OSAS Results for Placebo Trocar Scars 6.8 +/- 2.7; OSAS Results for 3 mg AZX100 Trocar Scars 6.8 +/- 2.5; OSAS Results for 10 mg AZX100 Trocar Scars 6.9 +/- 2.5 (p 0.57)
• Between-group Mean Differences in Visual Analog Scale Scores Rated by Independent Blinded Raters Using 3D Photography (Secondary), Mean, Millimeters: Rater 1 VAS Scores for Placebo Trocar Scars 10.96 +/- 8.58; Rater 1 VAS Scores for 3 mg AZX100 Trocar Scars 11.78 +/- 9.91; Rater 1 VAS Scores for 10 mg AZX100 Trocar Scars 11.86 +/- 7.21; Rater 2 VAS Scores for Placebo Trocar Scars 17.23 +/- 12.25; Rater 2 VAS Scores for 3 mg AZX100 Trocar Scars 17.49 +/- 11.66; Rater 2 VAS Scores for 10 mg AZX100 Trocar Scars 18.49 +/- 11.20 (p 0.47)
• Between-group Mean Differences in Objective Measures Via 3D Photography (Elevation, Length, Width) (Secondary), Mean, Millimeters: Scar Length for Placebo Trocar Scars 8.75 +/- 4.12; Scar Length for 3 mg AZX100 Trocar Scars 8.74 +/- 3.70; Scar Length for 10 mg AZX100 Trocar Scars 9.59 +/- 3.84; Scar Width for Placebo Trocar Scars 2.62 +/- 1.50; Scar Width for 3 mg AZX100 Trocar Scars 2.59 +/- 1.31; Scar Width for 10 mg AZX100 Trocar Scars 2.71 +/- 1.35; Scar Minimum Elevation for Placebo Trocar Scars -0.26 +/- 0.19; Scar Minimum Elevation for 3 mg AZX100 Trocar Scars -0.29 +/- 0.21; Scar Minimum Elevation for 10 mg AZX100 Trocar Scars -0.27 +/- 0.20; Scar Maximum Elevation for Placebo Trocar Scars 0.19 +/- 0.17; Scar Maximum Elevation for 3 mg AZX100 Trocar Scars 0.18 +/- 0.13; Scar Maximum Elevation for 10 mg AZX100 Trocar Scars 0.19 +/- 0.13 (p 0.87)
• Between-group Mean Differences in Objective Measures Via 3D Photography (Volume) (Secondary), Mean, Millimeters cubed: Scar Positive Volume for Placebo Trocar Scars 4.74 +/- 8.95; Scar Positive Volume for 3 mg AZX100 Trocar Scars 4.05 +/- 4.25; Scar Positive Volume for 10 mg AZX100 Trocar Scars 4.44 +/- 4.46; Scar Negative Volume for Placebo Trocar Scars -8.42 +/- 8.66; Scar Negative Volume for 3 mg AZX100 Trocar Scars -9.44 +/- 12.77; Scar Negative Volume for 10 mg AZX100 Trocar Scars -9.59 +/- 13.01; Scar Total Volume for Placebo Trocar Scars 13.16 +/- 11.53; Scar Total Volume for 3 mg AZX100 Trocar Scars 13.49 +/- 13.36; Scar Total Volume for 10 mg AZX100 Trocar Scars 14.03 +/- 13.68 (p 0.16)
• Histological Evaluation of Collagen (Secondary), Mean, Percent: Collagen Fiber Density Results for Placebo Scars 24.20 +/- 24.08; Collagen Fiber Density Results for 3 mg AZX100 Scars 19.43 +/- 21.79; Collagen Fiber Density Results for 10 mg AZX100 Scars 25.34 +/- 23.18; Collagen Fiber Maturity Results for Placebo Scars 22.72 +/- 23.59; Collagen Fiber Maturity Results for 3 mg AZX100 Scars 17.95 +/- 21.52; Collagen Fiber Maturity Results for 10 mg AZX100 Scars 23.64 +/- 22.68; Collagen Fiber Orientation Results for Placebo Scars 23.41 +/- 24.54; Collagen Fiber Orientation Results for 3 mg AZX100 Scars 18.52 +/- 21.73; Collagen Fiber Orientation Results for 10 mg AZX100 Scars 24.77 +/- 24.00 (p 0.086)
• Histological Evaluation of Number of Alpha Smooth Muscle Actin Cells (Secondary), Mean, Cells per high-powered field: Alpha SMA Results for Placebo Trocar Scars 22.07 +/- 47.02; Alpha SMA Results for 3 mg AZX100 Trocar Scars 24.78 +/- 58.25; Alpha SMA Results for 10 mg AZX100 Trocar Scars 32.80 +/- 64.56 (p 0.44)

Adverse events

Time frame: Adverse events began to be collected for each patient after dosing with study agent, and were collected for the duration of the study (12 months). The adverse event collection period for the entire study lasted for a period of 24 months.

Serious adverse events by term

Other adverse events by term