A Pilot Study of Apligraf for the Treatment and Prevention of Recurrence of Excised Keloids

• Sponsor: Organogenesis (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00587587
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Arms: 2
• Duration (Months): 27
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

This pilot study will assess the safety and efficacy of Apligraf in the healing and recurrence of keloids post surgical shave excision in patients with clinically diagnosed keloids.

Condition or Disease	Intervention/Treatment	Phase
Keloid	Device: Apligraf; Other: Standard dressing regimen	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective, Randomized, Controlled Pilot Study of Apligraf for the Treatment and Prevention of Recurrence of Excised Keloids
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A Apligraf (bilayered living cell therapy)	Device: Apligraf; Application at Day 0, potential re-application at Week 4
Active Comparator: B Dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary	Other: Standard dressing regimen; A primary nonadherent dressing, dry gauze dressing and bolster gauze dressing if necessary

Outcome Measures

Primary Outcome Measures

1. The Primary Purpose of This Study Will be to Gain Preliminary Safety Experience With Apligraf in the Keloid Indication. The Number of Participants Experiencing AEs is Presented. [52 weeks]

   Summary of all reported adverse events (AE) in the intent to treat (ITT) population. AE was defined as any adverse change in the subject's medical status compared with the subject's baseline condition, whether or not the event was related to the study device or a study procedure; or an exacerbation (either in frequency or severity) in a subject's pre-existing condition. AE data were collected at every study visit or if volunteered by the subject at any time during the study.

Secondary Outcome Measures

1. Change in Degree of Keloid Recurrence as Measured by Beausang Scar Scale (BSS) [Baseline to Week 52 or Last Visit]

   Change in BSS cumulative score, Baseline to Last Visit, as reported by the Investigator, is reported. BSS is a composite score where the individual scores from the following categories are summed: Color (rated 1[perfect]-4[gross mismatch]), Shine (1/Matte or 2/Shiny), Contour (rated 1[flush with surrounding skin]-4[keloid]), Distortion (rated 1[None]-4[severe]), Texture (rated 1[normal]-4[hard]), and Overall Assessment on a 10cm visual analog scale (rated 0[excellent scar]-10 [poor scar]). Total score ranges from 5 (clinically well healed scar) - 28 (clinically poor scar).

2. Cumulative Incidence of Keloid Recurrence at Week 52 [52 weeks]

   Recurrence is defined the first study visit at which the Investigator scores the Contour component of the BSS with a 4 (indicating a keloid). Contour is one of the five components measured in the BSS with Contour scores ranging from 1 (flush with surrounding skin) to 4 (keloid). Recurrence is a negative outcome.

3. Degree of Recurrence (Scar Firmness) [Week 52 or Last Visit]

   Scar firmness measured by Cutometer in millimeters.

4. Degree of Recurrence (Scar Thickness) [Week 52 or Last visit]

   Scar thickness measured by slide caliper in millimeters. A value of 0.0 mm on the slide caliper is equivalent to normal, non-hypertrophic/raised skin.

5. Physician Global Assessment [Week 52 or Last Visit]

   Investigator assessed using 5 point scale (1-excellent, 2-very good, 3-good, 4-moderate, 5-poor)

6. Subject Global Assessment [Week 52 or Last Visit]

   Subject assessed using 5 point scale (1-excellent, 2-very good, 3-good, 4-moderate, 5-poor)

7. Decreased Utilization of Intralesional Steroid Intervention [52 weeks]

   The mean number of Intralesional (IL) Injections per participant is reported. A lower number of injections is a better outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject is between 18 and 65 years of age.

• Subject or legal guardian has read, understood, and signed appropriate Institutional Review Board (IRB) approved informed consent, photography release form and HIPAA consent in their own language.

• Subject with 1 keloid measuring between 1 cm2 - 40 cm2 as assessed by the Investigator, present for at least 6 months and a Beausang Scar scale combined score of 5 or greater.

• Subject is a male or female who must have a documented negative urine pregnancy test if of child bearing potential. Sexually active females must be practicing a medically proven form of contraception during the course of the study period.

• Subject and/or legal guardian must be able and willing to follow study procedures and instructions.

• Subject and/or legal guardian must be able and willing to return for follow-up study visits.

• Subject agrees to not use a keloid medication or injection treatment for four weeks prior to Day 0.

• Subject agrees not to use any other keloid treatments for the duration of the study.

• Subject is otherwise healthy as assessed and determined by the Investigator

Exclusion Criteria:

• Subject is suffering from a condition likely to require medical attention, including administration of any treatment which in the opinion of the Investigator could influence the results of the study.

• Subject with any systemic condition like uncontrolled diabetes mellitus (glycosylated hemoglobin, HbA1C > 10%), cancer (biopsy confirming active malignancy), positive HIV test, or any disorder(s) that may compromise wound healing.

• Subject is suffering from an abnormal skin condition on the affected area not usually associated with keloids such as psoriasis, or eczema.

• Subject who is currently or has received topical or systemic steroid medication therapy within the past four weeks affecting the course of the keloid and/or its evaluability. Inhaled steroid therapy is acceptable.

• Subject with the presence of acute infections in the areas intended for treatment.

• Subject with known hypersensitivity to bovine collagen or to the components of the Apligraf agarose shipping medium.

• Subject who is lactating or pregnant (positive result as determined by urine testing).

• Subject with liver (ALT/SGPT, ALP, AST/SGOT, bilirubin, albumin, total protein, LDH) and/or renal function (BUN and creatinine) tests > 2 x upper limit of normal (ULN).

• Subject who has been previously enrolled in any wound or investigational device study for any disease within the past four weeks.

• Subject who has received an investigational drug or biological treatment within the past three months.

• Subject previously treated with Apligraf, Dermagraft or any other cell therapy at the target keloid site.

• Subject with a history of alcohol or substance abuse within the previous year, which could interfere with study compliance such as inability to attend scheduled study visits or compliance with home dressing changes.

• Subject with a history of anaphylaxis.

• Subject who, in the opinion of the Investigator, for any reason other than those listed above, will not be able to complete the study per protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Miami, Miller School of Medicine, Division of Cosmetic Dermatology	Miami Beach	Florida	United States	33140

Sponsors and Collaborators

• Organogenesis

Investigators

• Principal Investigator: Heather Woolery-Lloyd, MD, University of Miami, Miller School of Medicine, Division of Cosmetic Dermatology
• Study Director: Damien Bates, MD, PhD, FRACS (Plast.), Organogenesis Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00587587
• Other Study ID Numbers: 06-KEL-001-AG
• First Posted: Jan 7, 2008
• Last Update Posted: Aug 19, 2011
• Last Verified: Aug 1, 2011

• Additional relevant MeSH terms: Keloid; Recurrence

Study Results

Participant Flow

Arm/Group Title	Apligraf	Control
Arm/Group Description	Apligraf (bilayered living cellular construct) plus a dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary	Dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary
Period Title: Overall Study
STARTED	17	13
COMPLETED	11	12
NOT COMPLETED	6	1

Baseline Characteristics

Arm/Group Title	Apligraf	Control	Total
Arm/Group Description	Apligraf (bilayered living cellular construct) plus a dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary	Dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary	Total of all reporting groups
Overall Participants	17	13	30
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	17 100%	13 100%	30 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.7 (12.9)	36.7 (13.5)	34.4 (13.1)
Sex: Female, Male (Count of Participants)
Female	11 64.7%	10 76.9%	21 70%
Male	6 35.3%	3 23.1%	9 30%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 5.9%	1 7.7%	2 6.7%
Not Hispanic or Latino	16 94.1%	12 92.3%	28 93.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	16 94.1%	12 92.3%	28 93.3%
White	1 5.9%	1 7.7%	2 6.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	The Primary Purpose of This Study Will be to Gain Preliminary Safety Experience With Apligraf in the Keloid Indication. The Number of Participants Experiencing AEs is Presented.
Description	Summary of all reported adverse events (AE) in the intent to treat (ITT) population. AE was defined as any adverse change in the subject's medical status compared with the subject's baseline condition, whether or not the event was related to the study device or a study procedure; or an exacerbation (either in frequency or severity) in a subject's pre-existing condition. AE data were collected at every study visit or if volunteered by the subject at any time during the study.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

ITT analysis per protocol. Report of at least 1 treatment emergent AE.

Arm/Group Title	A (Apligraf)	B (Control)
Arm/Group Description	Apligraf (bilayered living cell therapy)	Dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary
Measure Participants	17	13
Any AE	12 70.6%	10 76.9%
Serious Adverse Event (SAE)	0 0%	0 0%
Unanticipated Adverse Device Effect (UADE)	0 0%	0 0%
Deaths	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A (Apligraf), B (Control)
	Comments	Fisher's exact test used to evaluate treatment differences between Apligraf subjects and Control subjects experiencing any AEs.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0000
	Comments	P-value compares overall incidence of AEs between groups, ie Apligraf 12/17 and Control 10/13. UADE is defined in 21CFR812.3(s)
	Method	Fisher Exact
	Comments

2. Secondary Outcome

Title	Change in Degree of Keloid Recurrence as Measured by Beausang Scar Scale (BSS)
Description	Change in BSS cumulative score, Baseline to Last Visit, as reported by the Investigator, is reported. BSS is a composite score where the individual scores from the following categories are summed: Color (rated 1[perfect]-4[gross mismatch]), Shine (1/Matte or 2/Shiny), Contour (rated 1[flush with surrounding skin]-4[keloid]), Distortion (rated 1[None]-4[severe]), Texture (rated 1[normal]-4[hard]), and Overall Assessment on a 10cm visual analog scale (rated 0[excellent scar]-10 [poor scar]). Total score ranges from 5 (clinically well healed scar) - 28 (clinically poor scar).
Time Frame	Baseline to Week 52 or Last Visit

Outcome Measure Data

Analysis Population Description

Modified ITT (mITT) for randomized subjects only. Last Visit is the score recorded at last subject visit with non-missing data.

Arm/Group Title	Apligraf	Control
Arm/Group Description	Apligraf (bilayered living cellular construct) plus a dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary	Dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary
Measure Participants	12	13
Mean (Standard Deviation) [Units on a scale]	-8.8 (5.1)	-9.7 (4.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A (Apligraf), B (Control)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5863
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Cumulative Incidence of Keloid Recurrence at Week 52
Description	Recurrence is defined the first study visit at which the Investigator scores the Contour component of the BSS with a 4 (indicating a keloid). Contour is one of the five components measured in the BSS with Contour scores ranging from 1 (flush with surrounding skin) to 4 (keloid). Recurrence is a negative outcome.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Cumulative assessment, mITT population for randomized subjects only

Arm/Group Title	Apligraf	Control
Arm/Group Description	Apligraf (bilayered living cellular construct) plus a dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary	Dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary
Measure Participants	12	13
Number [participants]	4 23.5%	2 15.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A (Apligraf), B (Control)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3783
	Comments
	Method	Fisher Exact
	Comments

4. Secondary Outcome

Title	Degree of Recurrence (Scar Firmness)
Description	Scar firmness measured by Cutometer in millimeters.
Time Frame	Week 52 or Last Visit

Outcome Measure Data

Analysis Population Description

mITT population (randomized subjects only). Last Visit is the score recorded at last subject visit with non-missing data.

Arm/Group Title	Apligraf	Control
Arm/Group Description	Apligraf (bilayered living cellular construct) plus a dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary	Dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary
Measure Participants	12	13
Mean (Standard Deviation) [mm]	0.2 (0.1)	0.2 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A (Apligraf), B (Control)
	Comments	Treatment differences in scar firmness evaluated using a 2-tailed Wilcoxon rank sum test with pooled variances.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7149
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Degree of Recurrence (Scar Thickness)
Description	Scar thickness measured by slide caliper in millimeters. A value of 0.0 mm on the slide caliper is equivalent to normal, non-hypertrophic/raised skin.
Time Frame	Week 52 or Last visit

Outcome Measure Data

Analysis Population Description

mITT population (randomized subjects only). Last Visit is the score recorded at last subject visit with non-missing data.

Arm/Group Title	A (Apligraf)	B (Control)
Arm/Group Description	Apligraf (bilayered living cell therapy)	Dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary
Measure Participants	12	13
Mean (Standard Deviation) [mm]	2.0 (2.2)	1.0 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A (Apligraf), B (Control)
	Comments	Treatment differences in scar thickness evaluated using a 2-tailed Wilcoxon rank sum test
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1670
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Physician Global Assessment
Description	Investigator assessed using 5 point scale (1-excellent, 2-very good, 3-good, 4-moderate, 5-poor)
Time Frame	Week 52 or Last Visit

Outcome Measure Data

Analysis Population Description

mITT population (randomized subjects only). Last Visit is the score recorded at last subject visit with non-missing data.

Arm/Group Title	Apligraf	Control
Arm/Group Description	Apligraf (bilayered living cellular construct) plus a dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary	Dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary
Measure Participants	12	13
Excellent	3 17.6%	3 23.1%
Very Good	3 17.6%	3 23.1%
Good	0 0%	2 15.4%
Moderate	5 29.4%	4 30.8%
Poor	1 5.9%	1 7.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A (Apligraf), B (Control)
	Comments	Global assessments analyzed as ordinal ranks. Treatment differences in global assessment evaluated using a 2-tailed Wilcoxon rank sum test with pooled variances.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7221
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Secondary Outcome

Title	Subject Global Assessment
Description	Subject assessed using 5 point scale (1-excellent, 2-very good, 3-good, 4-moderate, 5-poor)
Time Frame	Week 52 or Last Visit

Outcome Measure Data

Analysis Population Description

mITT population (randomized subjects only). Last Visit is the score recorded at last subject visit with non-missing data.

Arm/Group Title	Apligraf	Control
Arm/Group Description	Apligraf (bilayered living cellular construct) plus a dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary	Dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary
Measure Participants	12	13
Excellent	4 23.5%	6 46.2%
Very Good	1 5.9%	3 23.1%
Good	5 29.4%	2 15.4%
Moderate	2 11.8%	1 7.7%
Poor	0 0%	1 7.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A (Apligraf), B (Control)
	Comments	Global assessments analyzed as ordinal ranks. Treatment differences in global assessment evaluated using a 2-tailed Wilcoxon rank sum test with pooled variances.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4080
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

8. Secondary Outcome

Title	Decreased Utilization of Intralesional Steroid Intervention
Description	The mean number of Intralesional (IL) Injections per participant is reported. A lower number of injections is a better outcome.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

mITT population (randomized subjects only)

Arm/Group Title	Apligraf	Control
Arm/Group Description	Apligraf (bilayered living cellular construct) plus a dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary	Dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary
Measure Participants	12	13
Mean (Standard Deviation) [Injections per Participant]	4.0 (1.8)	4.2 (1.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A (Apligraf), B (Control)
	Comments	Differences evaluated using a 2-tailed Wilcoxon rank sum test with pooled variances.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9556
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Arm/Group Title	Apligraf		Control
Arm/Group Description	Apligraf (bilayered living cellular construct) plus a dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary		Dressing regimen comprised of a primary nonadherent dressing, dry gauze dressing and bolster gauze dressing, if necessary
All Cause Mortality
	Apligraf		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Apligraf		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Apligraf		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/17 (70.6%)		10/13 (76.9%)
Blood and lymphatic system disorders
Hypercoagulation	0/17 (0%)	0	1/13 (7.7%)	1
Gastrointestinal disorders
Abdominal pain	0/17 (0%)	0	1/13 (7.7%)	1
Diarrhoea	1/17 (5.9%)	1	0/13 (0%)	0
Gastroenteritis Viral	0/17 (0%)	0	1/13 (7.7%)	1
Nausea	1/17 (5.9%)	1	0/13 (0%)	0
Toothache	1/17 (5.9%)	1	0/13 (0%)	0
Vomiting	2/17 (11.8%)	2	0/13 (0%)	0
General disorders
Inflammation	0/17 (0%)	0	1/13 (7.7%)	1
Infections and infestations
Tinea Versicolour	1/17 (5.9%)	1	0/13 (0%)	0
Wound Infection	1/17 (5.9%)	1	0/13 (0%)	0
Wound Infection Bacterial	0/17 (0%)	0	1/13 (7.7%)	2
Injury, poisoning and procedural complications
Procedural Pain	0/17 (0%)	0	1/13 (7.7%)	2
Wound Complication	5/17 (29.4%)	8	7/13 (53.8%)	9
Wound Haemorrhage	1/17 (5.9%)	1	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/17 (0%)	0	1/13 (7.7%)	1
Nervous system disorders
Headache	3/17 (17.6%)	3	0/13 (0%)	0
Pregnancy, puerperium and perinatal conditions
Vomiting in Pregnancy	0/17 (0%)	0	1/13 (7.7%)	1
Psychiatric disorders
Insomnia	0/17 (0%)	0	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Influenza	1/17 (5.9%)	1	1/13 (7.7%)	1
Nasopharyngitis	3/17 (17.6%)	3	4/13 (30.8%)	4
Skin and subcutaneous tissue disorders
Seborrhoeic Dermatitis	1/17 (5.9%)	1	0/13 (0%)	0
Skin Irritation	0/17 (0%)	0	1/13 (7.7%)	1
Vascular disorders
Hypertension	0/17 (0%)	0	1/13 (7.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.