Phase II Clinical Trial of Intraoral Grafting of Human Tissue Engineered Oral Mucosa

• Sponsor: Stephen E. Feinberg (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01834326
• Collaborator: (none)
• Enrollment: 18
• Location: 1
• Arms: 2
• Duration (Months): 57.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to improve the current standard of care of repairing mouth soft tissue defects.

Condition or Disease	Intervention/Treatment	Phase
Disorder of Oral Mucous Membrane	Biological: EVPOME (autogenous ex vivo produced oral mucosa equivalent); Biological: POM (Palatal oral mucosa)	Phase 2

Detailed Description

This study will test a tissue equivalent ex vivo produced oral mucosa equivalent(EVPOME), which is a subject's own cells grown on top of a piece of AlloDerm (a commercially available freeze dried human cadaver tissue that is routinely used in present day surgical reconstructive procedures) to create a new piece of soft tissue for use only in that subject's body. The tissue equivalent product will be tested against a non-experimental method of grafts, the gold standard a piece of palatal oral mucosa (POM) to see which works best. Each subject will be randomly assigned to receive either the EVPOME or POM to cover the defect in their mouth. The objective of the study is to assess the safety and efficacy for the use of human EVPOME for soft tissue intraoral grafting procedures compared to the "gold standard" palatal oral mucosa (POM) graft.

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Parallel-group Autogenous ex Vivo Produced Oral Mucosa Equivalent vs. Palatal Oral Mucosa Safety and Efficacy Study in Subjects Requiring Additional Keratinized Oral Mucosa for Dental Implants
• Study Start Date: Apr 1, 2014
• Actual Primary Completion Date: Jan 15, 2019
• Actual Study Completion Date: Jan 15, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Palatal Oral Mucosa (POM) Graft Standard of care palatal oral mucosa (POM) graft will be taken from the palate and then surgically placed onto the defect area	Biological: POM (Palatal oral mucosa); POM is a tissue graft harvested from the palate and surgically placed into the defect area
Experimental: Ex vivo Produced Oral Mucosa Equivalent Palatal biopsy will be harvested for fabrication of autogenous ex vivo produced oral mucosa equivalent (EVPOME) and then surgically placed onto the defect area	Biological: EVPOME (autogenous ex vivo produced oral mucosa equivalent); EVPOME is manufactured from the subjects own oral cells and is implanted back in the subjects mouth after an approximately 30 day manufacturing process.

Outcome Measures

Primary Outcome Measures

1. Clinical Increase in Zone (Width) of Keratinized Mucosa at Grafted Site [2 and 4 weeks post surgical graft]

   The keratinized mucosa (KM) width will be measured by determining the distance from the crest of the edentulous ridge to the mucogingival line to the nearest millimeter with a Castroviejo caliper. The keratinized mucosa width of study subjects was measured prior to graft placement and then after two weeks, and after 4 weeks. The data provided shows the difference in keratinized mucosa width between the pre surgery measure and the post surgery measure. More mucosa width (positive numbers in mm) is an improvement, negative numbers (a decrease) would be less good.

Secondary Outcome Measures

1. Graft Contracture [2, 4, 8 and 24 weeks after surgery]

   Graft measurements collected at each time point post graft surgery, 2 weeks, 4 weeks, 8 weeks and 24 weeks. Measurements collected, Horizontal Coronal (mm), Horizontal Apical (mm), Vertical between coronal and apical (mm), were used to determine the area of the graft as a trapezoid like shape. The area of the graft at each time point was compared to the area of the graft at the time of implantation (graft surgery) to determine the % of graft contracture from implantation thru each follow-up time point. Less graft contracture is considered a better outcome.

Other Outcome Measures

1. Graft Blood Flow [2 and 4 weeks after surgery]

   Graft blood flow measured using Laser Doppler flowmetry (LDF) of the graft at 2 and 4 weeks after surgery. LDF measurements (perfusion units) are taken at the site of the graft and compared to LDF readings at a contralateral site on the same subject. The comparison is reported as a percent. The percent is derived by dividing the LDF perfusion units at the graft site by the LDF perfusion units at the contralateral site in the same subject. It is not known how many perfusion units are necessary to adequately supply blood to a graft. By comparing the graft site to the contralateral site in the same patient at 2 and 4 weeks post surgery this data may provide more understanding of graft incorporation.

2. Immunohistochemistry Using Anti-CD31 (Cluster of Differentiation 31) to Detect Blood Vessel Growth Into the Graft. [4 weeks after graft surgery]

   A biopsy of the graft is taken at 4 weeks after engraftment. The biopsy is stained for CD31 (cluster of differentiation 31) which is a marker for blood vessels. The number of blood vessels are counted in a standardized size of field. The number of blood vessels within the standardized field is reported. It is not known how much blood vessel development is necessary for graft success, but this study may provide insight into blood vessel development within EVPOME grafts over time.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Deficient band (<3mm) of keratinized mucosa prior to or following dental implant placement

• Surgery to increase width of keratinized mucosa is clinically indicated or requested by the patient to facilitate oral hygiene procedures or to improve esthetics

• Patients in need of a graft of approximately 15 x 10 x 20 mm in dimension

Exclusion Criteria:

• Subjects with potential medical complications such as evidence of clinically significant (as described by investigators) renal, hepatic, cardiac, endocrine, hematologic, autoimmune, or any systemic disease which may complication execution of the protocol and/or interpretation of results

• Current radiation therapy or history of radiation therapy treatment to the intraoral donor biopsy site or recipient site for graft placement

• Documented history of syphilis, HIV, Hepatitis B or C virus

• Pregnant women or women planning to become pregnant or unwilling to abstain or use double barrier contraceptives during the course of the study

• Smoking or use of tobacco products within 6 months prior to screening

• History of either alcohol or drug abuse

• Subjects taking medications that can result in gingival enlargement/overgrowth (Cyclosporine, Dilantin, calcium channel blockers)

• Current use of intravenous bisphosphonate or current oral bisphosphate use or a history of bisphosphonate use for over 5 years

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan, Department of Oral & Maxxillofacial Surgery	Ann Arbor	Michigan	United States	48109-5018

Sponsors and Collaborators

• Stephen E. Feinberg

Investigators

• Principal Investigator: Stephen E Feinberg, DDS, PhD, MS, University of Michigan

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 30, 2017
• Informed Consent Form - Jan 3, 2019

More Information

Publications

None provided.

• Responsible Party: Stephen E. Feinberg, Professor & Associate Chair of Research, University of Michigan
• ClinicalTrials.gov Identifier: NCT01834326
• Other Study ID Numbers: HUM00065554
• First Posted: Apr 17, 2013
• Last Update Posted: Sep 5, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Stephen E. Feinberg, Professor & Associate Chair of Research, University of Michigan: dental implants; deficient keratinized oral mucosa

Study Results

Participant Flow

Arm/Group Title	Palatal Oral Mucosa (POM) Graft	Ex Vivo Produced Oral Mucosa Equivalent
Arm/Group Description	Standard of care palatal oral mucosa (POM) graft will be taken from the palate and then surgically placed onto the defect area POM (Palatal oral mucosa): POM is a tissue graft harvested from the palate and surgically placed into the defect area	Palatal biopsy will be harvested for fabrication of autogenous ex vivo produced oral mucosa equivalent (EVPOME) and then surgically placed onto the defect area EVPOME (autogenous ex vivo produced oral mucosa equivalent): EVPOME is manufactured from the subjects own oral cells and is implanted back in the subjects mouth after an approximately 30 day manufacturing process.
Period Title: Overall Study
STARTED	10	8
COMPLETED	8	2
NOT COMPLETED	2	6

Baseline Characteristics

Arm/Group Title	Palatal Oral Mucosa (POM) Graft	Ex Vivo Produced Oral Mucosa Equivalent	Total
Arm/Group Description	Standard of care palatal oral mucosa (POM) graft will be taken from the palate and then surgically placed onto the defect area POM (Palatal oral mucosa): POM is a tissue graft harvested from the palate and surgically placed into the defect area	Palatal biopsy will be harvested for fabrication of autogenous ex vivo produced oral mucosa equivalent (EVPOME) and then surgically placed onto the defect area EVPOME (autogenous ex vivo produced oral mucosa equivalent): EVPOME is manufactured from the subjects own oral cells and is implanted back in the subjects mouth after an approximately 30 day manufacturing process.	Total of all reporting groups
Overall Participants	10	8	18
Age, Customized (Count of Participants)
Age 18 to 80 Years	10 100%	8 100%	18 100%
Sex/Gender, Customized (participants) [Number]
Male	4 40%	1 12.5%	5 27.8%
Female	6 60%	7 87.5%	13 72.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 10%	0 0%	1 5.6%
Not Hispanic or Latino	6 60%	8 100%	14 77.8%
Unknown or Not Reported	3 30%	0 0%	3 16.7%
Deficient band of keratinized mucosa (Count of Participants)
Count of Participants [Participants]	10 100%	8 100%	18 100%

Outcome Measures

1. Primary Outcome

Title	Clinical Increase in Zone (Width) of Keratinized Mucosa at Grafted Site
Description	The keratinized mucosa (KM) width will be measured by determining the distance from the crest of the edentulous ridge to the mucogingival line to the nearest millimeter with a Castroviejo caliper. The keratinized mucosa width of study subjects was measured prior to graft placement and then after two weeks, and after 4 weeks. The data provided shows the difference in keratinized mucosa width between the pre surgery measure and the post surgery measure. More mucosa width (positive numbers in mm) is an improvement, negative numbers (a decrease) would be less good.
Time Frame	2 and 4 weeks post surgical graft

Outcome Measure Data

Analysis Population Description

Pregraft data for this outcome was not collected for the first subject, the protocol was written to collect the pregraft measurement after the first subject completed POM graft. For this reason there are only 7 data points in the POM arm of the study.

Arm/Group Title	Palatal Oral Mucosa (POM) Graft	Ex Vivo Produced Oral Mucosa Equivalent
Arm/Group Description	Standard of care palatal oral mucosa (POM) graft will be taken from the palate and then surgically placed onto the defect area POM (Palatal oral mucosa): POM is a tissue graft harvested from the palate and surgically placed into the defect area	Palatal biopsy will be harvested for fabrication of autogenous ex vivo produced oral mucosa equivalent (EVPOME) and then surgically placed onto the defect area EVPOME (autogenous ex vivo produced oral mucosa equivalent): EVPOME is manufactured from the subjects own oral cells and is implanted back in the subjects mouth after an approximately 30 day manufacturing process.
Measure Participants	7	2
2 Week increase in keratinized mucosa	6.1 (1.9)	6.5 (2.1)
4 week increase in keratinized mucosa	5.1 (1.4)	4.5 (2.1)

2. Secondary Outcome

Title	Graft Contracture
Description	Graft measurements collected at each time point post graft surgery, 2 weeks, 4 weeks, 8 weeks and 24 weeks. Measurements collected, Horizontal Coronal (mm), Horizontal Apical (mm), Vertical between coronal and apical (mm), were used to determine the area of the graft as a trapezoid like shape. The area of the graft at each time point was compared to the area of the graft at the time of implantation (graft surgery) to determine the % of graft contracture from implantation thru each follow-up time point. Less graft contracture is considered a better outcome.
Time Frame	2, 4, 8 and 24 weeks after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Palatal Oral Mucosa (POM) Graft	Ex Vivo Produced Oral Mucosa Equivalent
Arm/Group Description	Standard of care palatal oral mucosa (POM) graft will be taken from the palate and then surgically placed onto the defect area POM (Palatal oral mucosa): POM is a tissue graft harvested from the palate and surgically placed into the defect area	Palatal biopsy will be harvested for fabrication of autogenous ex vivo produced oral mucosa equivalent (EVPOME) and then surgically placed onto the defect area EVPOME (autogenous ex vivo produced oral mucosa equivalent): EVPOME is manufactured from the subjects own oral cells and is implanted back in the subjects mouth after an approximately 30 day manufacturing process.
Measure Participants	8	2
2 weeks post surgery	10 (28)	24 (34)
4 weeks post surgery	31 (24)	49 (13)
8 weeks post surgery	45 (11)	73 (4)
24 weeks post surgery	42 (15)	71 (6)

3. Other Pre-specified Outcome

Title	Graft Blood Flow
Description	Graft blood flow measured using Laser Doppler flowmetry (LDF) of the graft at 2 and 4 weeks after surgery. LDF measurements (perfusion units) are taken at the site of the graft and compared to LDF readings at a contralateral site on the same subject. The comparison is reported as a percent. The percent is derived by dividing the LDF perfusion units at the graft site by the LDF perfusion units at the contralateral site in the same subject. It is not known how many perfusion units are necessary to adequately supply blood to a graft. By comparing the graft site to the contralateral site in the same patient at 2 and 4 weeks post surgery this data may provide more understanding of graft incorporation.
Time Frame	2 and 4 weeks after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Palatal Oral Mucosa (POM) Graft	Ex Vivo Produced Oral Mucosa Equivalent
Arm/Group Description	Standard of care palatal oral mucosa (POM) graft will be taken from the palate and then surgically placed onto the defect area POM (Palatal oral mucosa): POM is a tissue graft harvested from the palate and surgically placed into the defect area	Palatal biopsy will be harvested for fabrication of autogenous ex vivo produced oral mucosa equivalent (EVPOME) and then surgically placed onto the defect area EVPOME (autogenous ex vivo produced oral mucosa equivalent): EVPOME is manufactured from the subjects own oral cells and is implanted back in the subjects mouth after an approximately 30 day manufacturing process.
Measure Participants	8	2
2 Week post surgery percent of perfusion units at graft site vs contralateral site on same subject	202 (391)	30 (4)
4 week post surgery percent of perfusion units at graft site vs contralateral site on same subject	206 (234)	222 (210)

4. Other Pre-specified Outcome

Title	Immunohistochemistry Using Anti-CD31 (Cluster of Differentiation 31) to Detect Blood Vessel Growth Into the Graft.
Description	A biopsy of the graft is taken at 4 weeks after engraftment. The biopsy is stained for CD31 (cluster of differentiation 31) which is a marker for blood vessels. The number of blood vessels are counted in a standardized size of field. The number of blood vessels within the standardized field is reported. It is not known how much blood vessel development is necessary for graft success, but this study may provide insight into blood vessel development within EVPOME grafts over time.
Time Frame	4 weeks after graft surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Palatal Oral Mucosa (POM) Graft	Ex Vivo Produced Oral Mucosa Equivalent
Arm/Group Description	Standard of care palatal oral mucosa (POM) graft will be taken from the palate and then surgically placed onto the defect area POM (Palatal oral mucosa): POM is a tissue graft harvested from the palate and surgically placed into the defect area	Palatal biopsy will be harvested for fabrication of autogenous ex vivo produced oral mucosa equivalent (EVPOME) and then surgically placed onto the defect area EVPOME (autogenous ex vivo produced oral mucosa equivalent): EVPOME is manufactured from the subjects own oral cells and is implanted back in the subjects mouth after an approximately 30 day manufacturing process.
Measure Participants	8	2
Mean (Standard Deviation) [Number of blood vessels]	15 (5)	17 (7)

Adverse Events

Time Frame	Life of study, 3 years.
Arm/Group Title	Palatal Oral Mucosa (POM) Graft		Ex Vivo Produced Oral Mucosa Equivalent
Arm/Group Description	Standard of care palatal oral mucosa (POM) graft will be taken from the palate and then surgically placed onto the defect area POM (Palatal oral mucosa): POM is a tissue graft harvested from the palate and surgically placed into the defect area		Palatal biopsy will be harvested for fabrication of autogenous ex vivo produced oral mucosa equivalent (EVPOME) and then surgically placed onto the defect area EVPOME (autogenous ex vivo produced oral mucosa equivalent): EVPOME is manufactured from the subjects own oral cells and is implanted back in the subjects mouth after an approximately 30 day manufacturing process.
All Cause Mortality
	Palatal Oral Mucosa (POM) Graft		Ex Vivo Produced Oral Mucosa Equivalent
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/8 (0%)
Serious Adverse Events
	Palatal Oral Mucosa (POM) Graft		Ex Vivo Produced Oral Mucosa Equivalent
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Palatal Oral Mucosa (POM) Graft		Ex Vivo Produced Oral Mucosa Equivalent
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/10 (60%)		1/8 (12.5%)
Gastrointestinal disorders
Stomach flu	1/10 (10%)	1	0/8 (0%)	0
General disorders
Temporary numbness in throat due to anesthetic	1/10 (10%)	1	1/8 (12.5%)	1
Headache	1/10 (10%)	1	0/8 (0%)	0
Lack of energy with feeling of fever	1/10 (10%)	1	0/8 (0%)	0
Musculoskeletal and connective tissue disorders
Severed Tendon Right Bicep	1/10 (10%)	1	0/8 (0%)	0
Respiratory, thoracic and mediastinal disorders
Viral cold	1/10 (10%)	1	0/8 (0%)	0
Sinus Infection	1/10 (10%)	1	0/8 (0%)	0
Skin and subcutaneous tissue disorders
Herpes Labialis	1/10 (10%)	1	0/8 (0%)	0
Bruising, neck	1/10 (10%)	1	0/8 (0%)	0
Throbbing	1/10 (10%)	1	0/8 (0%)	0
Keratin nodule	1/10 (10%)	1	0/8 (0%)	0
Intra oral herpes	1/10 (10%)	1	0/8 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.