Trial Outcomes & Findings for Study Investigating the Safety and Efficacy of HP802-247 in the Treatment of Venous Leg Ulcers (NCT NCT01656889)

Last Updated: 2016-03-14

Results Overview

For each treatment group the area of each subject's target ulcer was measured on a weekly basis, for up to 12 weeks, using a laser-based wound imaging system in conjunction with software to measure area. Following initial closure subjects returned for four weekly visits to confirm wound closure. Wounds that remained closed for four weeks were classified as confirmed closures; if a wound opened at any of the 4 visits it was not considered to have closed. For subjects who dropped from the study, their remaining visit values were imputed using LOCF; wound status of closed was not imputed.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

447 participants

Primary outcome timeframe

12 Weeks

Results posted on

2016-03-14

Participant Flow

Subjects were screened at 43 sites in the US and 5 in Canada; between August 22, 2012 and April 18, 2014; sites included independent and hospital wound clinics and private practice sites.

Subjects entered a 2-week run-in; subjects whose wound radius decreased by \< 0.349 cm/2weeks and met all other inclusion/exclusion (I/E) criteria were eligible for randomization. After completion of the treatment period, subjects entered a three-month follow up period.

Participant milestones

Participant milestones
Measure	HP802-247 HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days. HP-802-247: HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days.	Vehicle Vehicle Control (fibrinogen solution \& thrombin solution without cells) Vehicle
Treatment Period, 12 Weeks STARTED	222	225
Treatment Period, 12 Weeks COMPLETED	210	214
Treatment Period, 12 Weeks NOT COMPLETED	12	11
Post Treatment Follow-Up, 3 Months STARTED	210	213
Post Treatment Follow-Up, 3 Months COMPLETED	206	204
Post Treatment Follow-Up, 3 Months NOT COMPLETED	4	9

Reasons for withdrawal

Reasons for withdrawal
Measure	HP802-247 HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days. HP-802-247: HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days.	Vehicle Vehicle Control (fibrinogen solution \& thrombin solution without cells) Vehicle
Treatment Period, 12 Weeks Adverse Event	10	4
Treatment Period, 12 Weeks Death	0	1
Treatment Period, 12 Weeks Lost to Follow-up	1	1
Treatment Period, 12 Weeks Withdrawal by Subject	1	2
Treatment Period, 12 Weeks Protocol Violation	0	1
Treatment Period, 12 Weeks Moved out of the area	0	2
Post Treatment Follow-Up, 3 Months Death	1	5
Post Treatment Follow-Up, 3 Months Lost to Follow-up	1	2
Post Treatment Follow-Up, 3 Months Withdrawal by Subject	2	1
Post Treatment Follow-Up, 3 Months Site Closure	0	1

Baseline Characteristics

Study Investigating the Safety and Efficacy of HP802-247 in the Treatment of Venous Leg Ulcers

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	HP802-247 n=211 Participants HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days. HP-802-247: HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days.	Vehicle n=210 Participants Vehicle Control (fibrinogen solution \& thrombin solution without cells) Vehicle	Total n=421 Participants Total of all reporting groups
Sex: Female, Male Female	71 Participants n=5 Participants	82 Participants n=7 Participants	153 Participants n=5 Participants
Sex: Female, Male Male	140 Participants n=5 Participants	128 Participants n=7 Participants	268 Participants n=5 Participants
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	136 Participants n=5 Participants	138 Participants n=7 Participants	274 Participants n=5 Participants
Age, Categorical >=65 years	75 Participants n=5 Participants	72 Participants n=7 Participants	147 Participants n=5 Participants
Age, Continuous	60.5 years STANDARD_DEVIATION 14.8 • n=5 Participants	61.0 years STANDARD_DEVIATION 12.5 • n=7 Participants	60.7 years STANDARD_DEVIATION 13.7 • n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	36 Participants n=5 Participants	42 Participants n=7 Participants	78 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	175 Participants n=5 Participants	168 Participants n=7 Participants	343 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Black or African American	43 Participants n=5 Participants	34 Participants n=7 Participants	77 Participants n=5 Participants
Race (NIH/OMB) White	160 Participants n=5 Participants	167 Participants n=7 Participants	327 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	7 Participants n=7 Participants	10 Participants n=5 Participants
Region of Enrollment Canada	9 participants n=5 Participants	13 participants n=7 Participants	22 participants n=5 Participants
Region of Enrollment United States	202 participants n=5 Participants	197 participants n=7 Participants	399 participants n=5 Participants

PRIMARY outcome

Timeframe: 12 Weeks

Population: ITT Populations: Subjects who received at least one dose of test article. Analysis was by the Cochrane Mantel Haenszel (CMH) test, adjusted for sites, with significance being at P \< 0.05

Outcome measures

Outcome measures
Measure	HP802-247 n=211 Participants HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days. HP-802-247: HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days.	Vehicle n=210 Participants Vehicle Control (fibrinogen solution \& thrombin solution without cells) Vehicle
Compare the Treatment Groups for the Proportion of Subjects With Complete Wound Closure Over the 12-Week Treatment Period From Baseline Wound Closed	129 participants	126 participants
Compare the Treatment Groups for the Proportion of Subjects With Complete Wound Closure Over the 12-Week Treatment Period From Baseline Wound Not Closed	82 participants	84 participants

SECONDARY outcome

Timeframe: 12 Weeks

Population: ITT Populations: Subjects who received at least one dose of test article. Data were analyzed using the Cox Proportional hazard procedure, with significance being at P \< 0.05 and by the Kaplan-Meier survival procedure

This key secondary outcome was based on a Cox Proportional Hazard Analysis and a Kaplan-Meier survival analysis.

Outcome measures

Outcome measures
Measure	HP802-247 n=211 Participants HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days. HP-802-247: HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days.	Vehicle n=210 Participants Vehicle Control (fibrinogen solution \& thrombin solution without cells) Vehicle
Compare the Efficacy of the Treatment Groups in Achieving Complete Wound Closure, Based on Time in Days to Closure Over the 12-Week Treatment Period From Baseline.	57.0 days Interval 8.0 to 115.0	50.0 days Interval 6.0 to 134.0

SECONDARY outcome

Timeframe: Weekly, over the 12 week treatment period, or until wound closure, which ever occurred first

Population: ITT Populations: Subjects who received at least one dose of test article. Analysis was by the Cochrane Mantel Haenszel (CMH) test, adjusted for sites, with significance being at P \< 0.05

Treatment groups were compared for the proportion of wounds closed at each weekly visit. For subjects who dropped from the study, their remaining visit values were imputed using LOCF.

Outcome measures

Outcome measures
Measure	HP802-247 n=211 Participants HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days. HP-802-247: HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days.	Vehicle n=210 Participants Vehicle Control (fibrinogen solution \& thrombin solution without cells) Vehicle
Compare the Treatment Groups for the Percentage of Closed Ulcers at Each Visit of the 12-Week Treatment Period From Baseline Baseline	0 percentage of Closed Ulcers	0 percentage of Closed Ulcers
Compare the Treatment Groups for the Percentage of Closed Ulcers at Each Visit of the 12-Week Treatment Period From Baseline Treatment Week 01	2.4 percentage of Closed Ulcers	1.9 percentage of Closed Ulcers
Compare the Treatment Groups for the Percentage of Closed Ulcers at Each Visit of the 12-Week Treatment Period From Baseline Treatment Week 02	5.7 percentage of Closed Ulcers	9.5 percentage of Closed Ulcers
Compare the Treatment Groups for the Percentage of Closed Ulcers at Each Visit of the 12-Week Treatment Period From Baseline Treatment Week 03	13.3 percentage of Closed Ulcers	19.5 percentage of Closed Ulcers
Compare the Treatment Groups for the Percentage of Closed Ulcers at Each Visit of the 12-Week Treatment Period From Baseline Treatment Week 04	23.7 percentage of Closed Ulcers	32.4 percentage of Closed Ulcers
Compare the Treatment Groups for the Percentage of Closed Ulcers at Each Visit of the 12-Week Treatment Period From Baseline Treatment Week 05	31.8 percentage of Closed Ulcers	38.1 percentage of Closed Ulcers
Compare the Treatment Groups for the Percentage of Closed Ulcers at Each Visit of the 12-Week Treatment Period From Baseline Treatment Week 06	38.9 percentage of Closed Ulcers	44.3 percentage of Closed Ulcers
Compare the Treatment Groups for the Percentage of Closed Ulcers at Each Visit of the 12-Week Treatment Period From Baseline Treatment Week 07	40.8 percentage of Closed Ulcers	47.6 percentage of Closed Ulcers
Compare the Treatment Groups for the Percentage of Closed Ulcers at Each Visit of the 12-Week Treatment Period From Baseline Treatment Week 08	46.4 percentage of Closed Ulcers	52.9 percentage of Closed Ulcers
Compare the Treatment Groups for the Percentage of Closed Ulcers at Each Visit of the 12-Week Treatment Period From Baseline Treatment Week 09	49.3 percentage of Closed Ulcers	55.2 percentage of Closed Ulcers
Compare the Treatment Groups for the Percentage of Closed Ulcers at Each Visit of the 12-Week Treatment Period From Baseline Treatment Week 10	53.6 percentage of Closed Ulcers	55.7 percentage of Closed Ulcers
Compare the Treatment Groups for the Percentage of Closed Ulcers at Each Visit of the 12-Week Treatment Period From Baseline Treatment Week 11	57.8 percentage of Closed Ulcers	60.0 percentage of Closed Ulcers
Compare the Treatment Groups for the Percentage of Closed Ulcers at Each Visit of the 12-Week Treatment Period From Baseline Treatment Week 12	63.0 percentage of Closed Ulcers	62.4 percentage of Closed Ulcers

SECONDARY outcome

Timeframe: Target ulcer status observed at two and three months following initial ulcer closure.

Population: The 285 subjects (HP802-247: 141/222; Vehicle: 144/225) who completed the treatment period with confirmed wound closure. Subjects returning for Visit 1 with confirmed wound closure at end of treatment: 134 HP802-247 and 132 Vehicle. Subjects returning for Visit 2 with confirmed wound closure at end of treatment: 132 HP802-247 and 131 Vehicle

Subjects who completed the treatment period with confirmed wound closure were followed in the post-treatment period for a further two months to determine their closed wound status (remained closed/reopened), giving a measure of persistence of wound closure following completion of treatment.

Outcome measures

Outcome measures
Measure	HP802-247 n=134 Participants HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days. HP-802-247: HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days.	Vehicle n=132 Participants Vehicle Control (fibrinogen solution \& thrombin solution without cells) Vehicle
Number of Subjects With Durable Wound Healing Over the 3 Months Following Complete Wound Closure Follow-up Visit 1 (2 months), Wounds Closed	120 participants	114 participants
Number of Subjects With Durable Wound Healing Over the 3 Months Following Complete Wound Closure Follow-up Visit 1 (2 months), Wounds Reopened	14 participants	18 participants
Number of Subjects With Durable Wound Healing Over the 3 Months Following Complete Wound Closure Follow-up Visit 2 (3 months), Wounds Closed	118 participants	112 participants
Number of Subjects With Durable Wound Healing Over the 3 Months Following Complete Wound Closure Follow-up Visit 2 (3 months), Wounds Reopened	14 participants	16 participants

SECONDARY outcome

Timeframe: Weekly, over the 12 week treatment period, baseline

Population: ITT Populations: Subjects who received at least one dose of test article. Data were analyzed by an ANCOVA, adjusted for site and baseline score.

Target leg pain were measured using a Visual Analog Scale \[Range: 0mm - 100mm\]. Subjects marked their pain level on a 100 mm horizontal line, with a short vertical line across the scale, 0 denoting no pain and 100mm the maximum pain.

Outcome measures

Outcome measures
Measure	HP802-247 n=210 Participants HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days. HP-802-247: HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days.	Vehicle n=210 Participants Vehicle Control (fibrinogen solution \& thrombin solution without cells) Vehicle
Change in Pain Associated With the Target Leg at Each of the 12 Double Blind Treatment Weeks Week 01	-3.74 units on a scale Standard Error 1.22	-2.19 units on a scale Standard Error 1.22
Change in Pain Associated With the Target Leg at Each of the 12 Double Blind Treatment Weeks Week 02	-4.18 units on a scale Standard Error 1.39	-4.03 units on a scale Standard Error 1.38
Change in Pain Associated With the Target Leg at Each of the 12 Double Blind Treatment Weeks Week 03	-6.14 units on a scale Standard Error 1.4	-5.91 units on a scale Standard Error 1.39
Change in Pain Associated With the Target Leg at Each of the 12 Double Blind Treatment Weeks Week 04	-8.2 units on a scale Standard Error 1.42	-6.71 units on a scale Standard Error 1.41
Change in Pain Associated With the Target Leg at Each of the 12 Double Blind Treatment Weeks Week 05	-10.6 units on a scale Standard Error 1.38	-8.62 units on a scale Standard Error 1.37
Change in Pain Associated With the Target Leg at Each of the 12 Double Blind Treatment Weeks Week 06	-11.04 units on a scale Standard Error 1.53	-8.2 units on a scale Standard Error 1.52
Change in Pain Associated With the Target Leg at Each of the 12 Double Blind Treatment Weeks Week 07	-11.57 units on a scale Standard Error 1.54	-9.77 units on a scale Standard Error 1.53
Change in Pain Associated With the Target Leg at Each of the 12 Double Blind Treatment Weeks Week 08	-11.18 units on a scale Standard Error 1.53	-10.65 units on a scale Standard Error 1.53
Change in Pain Associated With the Target Leg at Each of the 12 Double Blind Treatment Weeks Week 09	-12.7 units on a scale Standard Error 1.5	-11.26 units on a scale Standard Error 1.49
Change in Pain Associated With the Target Leg at Each of the 12 Double Blind Treatment Weeks Week 10	-12.55 units on a scale Standard Error 1.52	-11.2 units on a scale Standard Error 1.51
Change in Pain Associated With the Target Leg at Each of the 12 Double Blind Treatment Weeks Week 11	-12.35 units on a scale Standard Error 1.49	-11.56 units on a scale Standard Error 1.48
Change in Pain Associated With the Target Leg at Each of the 12 Double Blind Treatment Weeks Week 12	-12.1 units on a scale Standard Error 1.49	-12.27 units on a scale Standard Error 1.48

SECONDARY outcome

Timeframe: Weekly, over 12 week treament period, baseline

Population: ITT Populations: Subjects who received at least one dose of test article. Data were analyzed by an ANCOVA, adjusted for site and baseline score.

Target ulcer pain were measured using a Visual Analog Scale \[Range: 0mm - 100mm\]. Subjects marked their pain level on a 100 mm horizontal line, with a short vertical line across the scale, 0 denoting no pain and 100mm the maximum pain.

Outcome measures

Outcome measures
Measure	HP802-247 n=210 Participants HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days. HP-802-247: HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days.	Vehicle n=210 Participants Vehicle Control (fibrinogen solution \& thrombin solution without cells) Vehicle
Change in Target Ulcer Pain Week 01	-5.08 units on a scale Standard Error 1.08	-5.05 units on a scale Standard Error 1.08
Change in Target Ulcer Pain Week 02	-7.59 units on a scale Standard Error 1.25	-6.95 units on a scale Standard Error 1.24
Change in Target Ulcer Pain Week 03	-10.32 units on a scale Standard Error 1.27	-9.58 units on a scale Standard Error 1.26
Change in Target Ulcer Pain Week 04	-12.17 units on a scale Standard Error 1.3	-10.26 units on a scale Standard Error 1.29
Change in Target Ulcer Pain Week 05	-13.15 units on a scale Standard Error 1.23	-13.17 units on a scale Standard Error 1.22
Change in Target Ulcer Pain Week 06	-15.56 units on a scale Standard Error 1.35	-13.03 units on a scale Standard Error 1.34
Change in Target Ulcer Pain Week 07	-15.8 units on a scale Standard Error 1.38	-14.51 units on a scale Standard Error 1.37
Change in Target Ulcer Pain Week 08	-16.28 units on a scale Standard Error 1.38	-14.81 units on a scale Standard Error 1.37
Change in Target Ulcer Pain Week 09	-17.16 units on a scale Standard Error 1.32	-15.97 units on a scale Standard Error 1.31
Change in Target Ulcer Pain Week 10	-17.65 units on a scale Standard Error 1.32	-15.91 units on a scale Standard Error 1.31
Change in Target Ulcer Pain Week 11	-17.34 units on a scale Standard Error 1.33	-16.47 units on a scale Standard Error 1.32
Change in Target Ulcer Pain Week 12	-17.18 units on a scale Standard Error 1.36	-16.39 units on a scale Standard Error 1.35

SECONDARY outcome

Timeframe: 12 weeks

Population: ITT Populations: Subjects who received at least one dose of test article. Data were analyzed using a Kaplan-Meier Survival Analysis, with significance being at P \< 0.05.

This key secondary outcome was based on a Kaplan-Meier survival analysis.

Outcome measures

Outcome measures
Measure	HP802-247 n=211 Participants HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days. HP-802-247: HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days.	Vehicle n=210 Participants Vehicle Control (fibrinogen solution \& thrombin solution without cells) Vehicle
Compare the Efficacy of the Treatment Groups in Achieving Complete Wound Closure, Based on the Median Time (in Days) to Closure Over the 12-Week Treatment Period From Baseline.	57.0 days to wound closure Interval 8.0 to 115.0	50.0 days to wound closure Interval 6.0 to 134.0

Adverse Events

HP802-247

Serious events: 17 serious events

Other events: 119 other events

Deaths: 0 deaths

Vehicle

Serious events: 21 serious events

Other events: 107 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Jaime E Dickerson, PhD

Smith & Nephew

Phone: 1-817-302-3914

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	HP802-247 n=222 participants at risk HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days. HP-802-247: HP802-247 (fibrinogen solution \& thrombin solution containing living, irradiated, growth arrested keratinocytes and fibroblasts) 260 µL (130 µL, one spray, of each solution) containing 0.5 x 106 cells per mL every 14 days.	Vehicle n=225 participants at risk Vehicle Control (fibrinogen solution \& thrombin solution without cells) Vehicle
Gastrointestinal disorders Gastrointestinal Disorders	3.2% 7/222 • Number of events 9 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	3.6% 8/225 • Number of events 8 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.
General disorders General disorders and administration site conditions	6.3% 14/222 • Number of events 15 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	4.9% 11/225 • Number of events 14 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.
Infections and infestations Cellulitis	3.6% 8/222 • Number of events 8 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	4.4% 10/225 • Number of events 15 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.
Infections and infestations Wound infection	2.7% 6/222 • Number of events 6 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	3.1% 7/225 • Number of events 8 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.
Injury, poisoning and procedural complications Injury, poisoining and procedural complication	12.2% 27/222 • Number of events 31 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	9.8% 22/225 • Number of events 24 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.
Injury, poisoning and procedural complications Wound complication	4.1% 9/222 • Number of events 9 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	5.8% 13/225 • Number of events 14 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.
Infections and infestations Infections and Infestations	17.6% 39/222 • Number of events 48 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	17.8% 40/225 • Number of events 58 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.
Metabolism and nutrition disorders Metabolism and Nutrition Disorders	4.1% 9/222 • Number of events 10 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	1.8% 4/225 • Number of events 5 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.
Musculoskeletal and connective tissue disorders Musculoskeletal and Connective Tissue Disorders	8.6% 19/222 • Number of events 23 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	8.0% 18/225 • Number of events 23 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.
Musculoskeletal and connective tissue disorders Pain in Extremity	6.8% 15/222 • Number of events 17 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	4.4% 10/225 • Number of events 10 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.
Nervous system disorders Nervous System Disorders	5.0% 11/222 • Number of events 12 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	3.6% 8/225 • Number of events 9 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.
Skin and subcutaneous tissue disorders Skin and Subcutaneous Tissue Disorders	32.0% 71/222 • Number of events 99 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	22.2% 50/225 • Number of events 75 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.
Skin and subcutaneous tissue disorders Rash	3.2% 7/222 • Number of events 7 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	0.44% 1/225 • Number of events 1 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.
Skin and subcutaneous tissue disorders Skin Ulcer	18.9% 42/222 • Number of events 53 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	13.8% 31/225 • Number of events 44 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.
Skin and subcutaneous tissue disorders Venous Ulcer Pain	3.2% 7/222 • Number of events 9 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	1.8% 4/225 • Number of events 5 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.
Vascular disorders Vascular Disorders	5.0% 11/222 • Number of events 13 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.	3.6% 8/225 • Number of events 10 • Up to 19 Weeks or subjects who completed 12 weeks of treatment and the post-treatment follow up. For subjects who had wound closure, collection time included the treatment period and the post-treatment period All subjects randomized to treatment were questioned about AE and were included in the number of participants assessed for safety. The first assessments at each weekly visit were about changes in general health and concomitant medications and the occurrence of AE. Some AE were only collected with respect to the organ system class.