Esthetic Outcomes Following Immediate Implant Combine With Soft Tissue Augmentation
Phase: PHASE4
Conditions: Dental Implant, Immediate Dental Implant, Soft Tissue Augmentation
Sponsor: The University of Texas Health Science Center, Houston

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Esthetic Outcomes Following Immediate Implant Combine with Soft Tissue 
Augmentation 
 
NCT02864862 
 
Version Date: 05/13/2016 
 
 

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STUDY PROTOCOL 
 
PROTOCOL NUMBER: 
HSC-DB-16-0286 
PROTOCOL TITLE: 
Esthetic Outcomes Following Immediate Implant Combine with Soft Tissue 
Augmentation 
VERSION: 
1 
DATE: 
03.14.2016 
CORRESPONDING PRINCIPAL INVESTIGATOR: 
Chun-Teh Lee, Assistant Professor, UTHealth School of Dentistry 
SITE PRINCIPAL INVESTIGATOR: 
Chun-Teh Lee, Assistant Professor, UTHealth School of Dentistry 
Robin Weltman, Associate Professor, UTHealth School of Dentistry 
Pedro Trejo, Clinical Associate Professor, UTHealth School of Dentistry/ Periodontal and 
Implant Surgeons of Houston 
SITE: 
1. UTHealth School of Dentistry, 7500 Cambridge street, Houston, TX 77054 
2. Periodontal and Implant Surgeons of Houston, 2600 South Gessner Road, Suite 
304, Houston, TX 77063 
COLLABORATORS: 
Nikola Angelov, Professor, UTHealth School of Dentistry 
Srinivas Ayilavarapu, Associate Professor, UTHealth School of Dentistry 
Aniket Jadhav, Assistant Professor, UTHealth School of Dentistry 
Liang Zhu, Associate Professor, UTHelath Medical School 

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GENERAL INFORMATION 
 
 
Name and address of the sponsor of the study: 
Not applicable 
Name and address of the person authorized to sign the protocol and amendments: 
Chun-Teh Lee, 7500 Cambridge Street, Suite 6422, Houston, Texas 77054 
Robin Weltman, 7500 Cambridge Street, Suite 6426, Houston, Texas 77054 
Pedro Trejo,2600 South Gessner Road, Suite 304, Houston, TX 77063 
Name, title, address and telephone number(s) of the medical expert for the trial 
Chun-Teh Lee, 7500 Cambridge Street, Suite 6422, Houston, Texas 77054 
Office: 713.486.4384; Cell: 6263798070 
Robin Weltman, 7500 Cambridge Street, Suite 6426, Houston, Texas 77054 
Office: 713.486.4382 
Nikola Angelov, 7500 Cambridge Street, Suite 6428, Houston, Texas 77054 
Office: 713.486.4073 
Pedro Trejo,2600 South Gessner Road, Suite 304, Houston, TX 77063 
Office: 713.785.4867 
Name and title of the investigator(s) and sub-investigators responsible for the trial 
with address and phone number(s) 
Chun-Teh Lee, 7500 Cambridge Street, Suite 6422, Houston, Texas 77054 
Office: 713.486.4384; Cell: 6263798070 
Robin Weltman, 7500 Cambridge Street, Suite 6426, Houston, Texas 77054 
Office: 713.486.4382 
Pedro Trejo,2600 South Gessner Road, Suite 304, Houston, TX 77063 
Office: 713.785.4867 

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TABLE OF CONTENTS 
1. 
BACKGROUND AND RATIONALE ........................................................................................ 5 
1.1. 
GENERAL INTRODUCTION ....................................................................................................................... 5 
1.2. 
RATIONALE AND JUSTIFICATION FOR THE STUDY ............................................................................... 6 
A. 
RATIONALE FOR THE STUDY PURPOSE ..................................................................................................... 7 
B. 
RATIONALE FOR DOSES SELECTED ........................................................................................................... 7 
C. 
RATIONALE FOR STUDY POPULATION ........................................................................................................ 7 
D. 
RATIONALE FOR STUDY DESIGN ................................................................................................................. 7 
2. 
HYPOTHESIS AND OBJECTIVES ......................................................................................... 8 
2.1. 
HYPOTHESIS .............................................................................................................................................. 8 
2.4. 
POTENTIAL RISKS AND BENEFITS .......................................................................................................... 8 
A. 
END POINTS - EFFICACY .............................................................................................................................. 8 
B. 
END POINTS - SAFETY .................................................................................................................................. 8 
3.1. 
LIST THE NUMBER OF SUBJECTS TO BE ENROLLED ............................................................................. 9 
3.2. 
CRITERIA FOR RECRUITMENT ................................................................................................................ 9 
3.3. 
INCLUSION CRITERIA ................................................................................................................................ 9 
3.4. 
EXCLUSION CRITERIA ............................................................................................................................ 10 
3.5. 
WITHDRAWAL CRITERIA ........................................................................................................................ 10 
3.6. 
SUBJECT REPLACEMENT....................................................................................................................... 10 
4. 
TRIAL SCHEDULE ................................................................................................................ 10 
5. 
STUDY DESIGN ................................................................................................................ 10 
5.1. 
SUMMARY OF STUDY DESIGN .............................................................................................................. 11 
6. 
METHODS AND ASSESSMENTS ........................................................................................ 11 
6.1. 
RANDOMIZATION AND BLINDING .......................................................................................................... 11 
6.2. 
CONTRACEPTION AND PREGNANCY TESTING ................................................................................... 11 
6.3. 
STUDY VISITS AND PROCEDURES ....................................................................................................... 11 
7. 
TRIAL MATERIALS .............................................................................................................. 14 
7.1. 
TRIAL PRODUCT (S) ......................................................................................................... 14 
7.2. 
STORAGE AND DRUG ACCOUNTABILITY ............................................................................................. 15 
8. 
TREATMENT ......................................................................................................................... 15 
8.1. 
RATIONALE FOR SELECTION OF DOSE ............................................................................................... 15 
8.2. 
STUDY DRUG FORMULATIONS ................................................. ERROR! BOOKMARK NOT DEFINED. 
8.3. 
STUDY DRUG ADMINISTRATION ............................................... ERROR! BOOKMARK NOT DEFINED. 
8.4. 
SPECIFIC RESTRICTIONS / REQUIREMENTS ...................................................................................... 15 
8.5. 
BLINDING .................................................................................................................................................. 15 
8.6. 
CONCOMITANT THERAPY ........................................................... ERROR! BOOKMARK NOT DEFINED. 
9. 
SAFETY MEASUREMENTS ................................................................................................. 16 
9.1. 
DEFINITIONS ............................................................................................................................................ 16 
9.2. 
COLLECTING, RECORDING AND REPORTING OF ADVERSE EVENTS ............................................. 16 
9.3. 
SAFETY MONITORING PLAN ................................................................................................................. 17 
10. 
DATA ANALYSIS.............................................................................................................. 17 
10.1. 
DATA QUALITY ASSURANCE ................................................................................................................. 17 
10.2. 
DATA ENTRY AND STORAGE ................................................................................................................ 17 
11. 
SAMPLE SIZE AND STATISTICAL METHODS .............................................................. 18 
11.1. 
DETERMINATION OF SAMPLE SIZE ...................................................................................................... 18 
11.2. 
STATISTICAL AND ANALYTICAL PLANS ................................................................................................ 18 
12. 
ETHICAL CONSIDERATIONS ......................................................................................... 19 

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12.1. 
INFORMED CONSENT ............................................................................................................................. 19 
12.2. 
IRB REVIEW ............................................................................................................................................. 20 
12.3. 
CONFIDENTIALITY OF DATA AND PATIENT RECORDS....................................................................... 20 
13. 
PUBLICATIONS ................................................................................................................ 20 
14. 
RETENTION OF TRIAL DOCUMENTS ............................................................................ 20 

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STUDY PROTOCOL 
 
 
1. 
BACKGROUND AND RATIONALE 
1.1. 
General Introduction 
The concept of immediate implant was proposed about forty years ago (Schulte 
and Heimke 1976; Schulte et al. 1978). Over the past few decades, several clinical 
trials had demonstrated immediate implantation has high survival rate and stable 
interproximal bone levels (Becker et al. 1998; Chen et al. 2007; Lazzara 1989; Sanz 
et al. 2014; Schropp et al. 2003), similar to conventional delayed implant placement. 
Compared to delayed placement, immediate implantation is able to reduce the 
number of clinical visits and surgical procedures, by this diminishing patient morbidity, 
and in some cases, enabling immediate restoration (Lang et al. 2012). In addition to 
these advantages, it has been suggested that immediate implant preserves alveolar 
bone dimensions (Denissen et al. 1993; Lazzara 1989; Paolantonio et al. 2001; 
Watzek et al. 1995). However, several experimental studies and clinical trials 
demonstrated significant changes of bony ridge dimensions in the surgical site of 
immediate implantation (Botticelli et al. 2004; Botticelli et al. 2006). 
Generally, the dimensional change of buccal site is greater than that of the lingual/ 
palatal site (Botticelli et al. 2004; Brownfield and Weltman 2012; Lee et al. 2014). The 
buccal bone(Lee et al. 2014) or buccal ridge dimensional alteration (Grunder 2011; 
van Kesteren et al. 2010) following immediate implant placement without placing any 
bone graft or tissue graft is about 1 to 1.5 mm within one year follow-up. The change 
of bone/ridge dimension also accompanies with gingival recession. The mean mid- 
buccal gingival recession is approximately 0.5 to 1mm within one year follow-up 
following immediate implantation and advanced mid-buccal gingival recession (>1 
mm) sometimes happens (Cosyn et al. 2012). Many clinicians try to prevent the 
changes of soft tissue and hard tissue in the esthetic demanding sites by using 
different methods. The effect of placing bone grafts and/or immediate temporization 
has been proved on compensating soft tissue and hard tissue collapse (Cosyn et al. 
2012; Tarnow et al. 2014). However, the use of autogenous tissue graft or alternative 
graft, such as collagen matrix and acelluar dermal matrix, combined with immediate 
implant is equivocal. 
Some experimental studies (Berglundh and Lindhe 1996) and clinical studies 
(Linkevicius et al. 2009; Linkevicius et al. 2014; Vervaeke et al. 2014) showed tissue 
thickness is negatively associated with the resorption of alveolar bone following 
implant placement. Therefore, augmenting soft tissue by tissue graft or acellular 
dermal matrix in the immediate implantation site may prevent the resorption of bone. 
The limited change of alveolar bone level also prevents gingival recession. 
Additionally, soft tissue augmentation combined with immediate implantation can 
directly compensate the dimensional alteration of ridge following extraction (Grunder 
2011) and also increases width of keratinized gingiva by two-stage approach (Covani 
et al. 2007; Jyothi et al. 2013). 
Autogenous soft tissue graft has been utilized in ridge augmentation(Allen et al. 
1985; Studer et al. 2000), root coverage(Cairo et al. 2014; Langer and Langer 1985), 
extension of keratinized gingival width (Cairo et al. 2014), gingival thickness 
augmentation(Muller et al. 1998), and as a barrier in wound healing (Ellegaard et al. 

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1974; Nelson 2001). Subepithelial connective tissue graft (SCTG) or free gingival 
graft (FGG) is usually harvested from palate (Langer and Langer 1985; Sullivan and 
Atkins 1968) given palate provides a large area of keratinized tissue. A number of 
studies have demonstrated clinical superiority of autogenous soft tissue grafts 
compared to the available substitutes used in procedures of root coverage 
(Chambrone et al. 2010; Oates et al. 2003) and keratinized gingiva 
augmentation(Thoma et al. 2009). 
In implant therapy, soft tissue grafts are utilized in ridge reconstruction (Grunder 
2000), coverage of crown margins or implant surface (Burkhardt et al. 2008; Lee et 
al. 2015a), and keratinized tissue extension (Stimmelmayr et al. 2011; Yan et al. 
2006). Soft tissue grafts have also been employed to seal extraction socket following 
immediate implant placement and at the same time to increase the width of 
keratinized gingiva (Edel 1995; Evian and Cutler 1994; Landsberg and Bichacho 
1994; Rosenquist 1997). Combination therapy of soft tissue and osseous grafting 
with or without a barrier in conjunction with immediate implantation has been 
proposed by several clinicians to address vertical and horizontal ridge dimensional 
reduction (Grunder 2011), gingival recession(Migliorati et al. 2015; Yoshino et al. 
2014) and to increase width of keratinized gingiva (Covani et al. 2007; Jyothi et al. 
2013). These procedures primarily aim to improve the esthetic outcomes following 
immediate implant placement. 
A range of biomaterials, including acellular dermal matrix and xenogeneic collagen 
matrix, have been developed to replace autogenous soft tissue grafts and to reduce 
patient morbidity. AlloDerm® Regenerative Tissue Matrix (RTM) is one of the most 
widely used alternative tissue grafts in dentistry. It is an acellular dermal matrix 
(ADM) that is derived from donated human skin and is minimally processed to 
remove epidermal and dermal cells with nondenaturing detergent while preserving 
the extracellular matrix. The removal of viable cells and antigens during the 
decellularization process minimizes the risk of rejection and inflammation at the 
surgical site. Then, a cyropreservant is added to avoid crystal formation, and then 
resulting tissue matrix is freeze-dried. The remaining matrix serves as a framework 
for cellular infiltration and vascularization. ADM is indicated for soft tissue 
augmentation (Batista et al. 2001; Griffin et al. 2004; Park and Wang 2006), gingival 
recession defect coverage (Andrade et al. 2008; Tal et al. 2002), keratinized gingiva 
extension (Harris 2001; Yan et al. 2006), and extraction socket coverage (Fowler et 
al. 2000; Froum et al. 2004; Park 2011) for both teeth and implants. Basically, ADM 
can be used in all the procedures that the soft tissue graft is indicated for. 
Although the application of soft tissue augmentation combined with immediate 
implant has been reported in some studies, there are only few studies directly 
comparing the esthetic outcomes of immediate implant combined with soft tissue 
augmentation to immediate implant alone (Lee et al. 2015b). The evidence regarding 
the clinical effects of placing acellular dermal matrix at the site of immediate implant 
is less. It is necessary to conduct a clinical trial evaluating the impact of immediate 
implant combined with or without soft tissue augmentation on preserving tissue 
contour. 
1.2. 
Rationale and justification for the Study 

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a. 
Rationale for the Study Purpose 
The results of a current systematic review indicated immediate implant combined 
with autogenous tissue graft is able to maintain the level of gingiva, increase gingival 
thickness and extend the width of keratinized gingiva (Lee et al. 2015b). However, 
there is lack of clinical trials directly comparing the esthtics-related clinical outcomes 
of immediate implant combined with or without soft tissue augmentation. 
The purpose of the randomized controlled trial is to evaluate the esthetic 
outcomes following immediate implant combined with the autogenous tissue graft or 
acellular dermal matrix compared to immediate implant alone. Changes of ridge 
dimension, gingival level, gingival thickness, width of keratinized tissue and bony 
structure will be assessed. SCTG is utilized instead of FGG because SCTG has less 
morbidity of the donor site and better esthetic outcomes than FGG (Del Pizzo et al. 
2002). ADM is utilized because it is the one of the most widely chosen substitutes for 
autogenous tissue graft in all kinds of procedure and has many published clinical 
results (Gapski et al. 2005). 
b. Rationale for Materials Selected 
SCTG will be harvested from the palate and the required size depends on the size 
of the surgical site. Generally, the width of the tissue graft should be sufficient to 
cover the adjacent interproximal papillae, and the length could be standardized as 10 
mm. The size of the tissue graft is able to cover the area usually having the most 
significant dimensional changes following extraction (Morimoto et al. 2015; Tarnow et 
al. 2014). The thickness of harvested tissue graft will be trimmed to the range from 1- 
1.5 mm (Hurzeler and Weng 1999). 
The ADM is a commercial product and has multiple sizes available. One piece of 
10mmx10mm ADM can be trimmed to an appropriate size defined by the criteria for 
SCTG. According to the manual instruction, the thickness of ADM ranges from 0.9- 
1.6mm which will be close to the thickness of SCTG utilized in this study. 
c. 
Rationale for Study Population 
The study will recruit subjects who have single unrestorable tooth planned for an 
implant placement. The tooth should have acceptable periodontal condition and 
locates in the oral esthetic zone, maxillary premolars to premolars. The surgical sites 
should have intact bony wall, but minor dehiscence or fenestration, up to 3mm, is 
allowed. These criteria justify the evaluation of esthetic outcomes in the site of 
immediate implantation. 
. 
d. 
Rationale for Study Design 
The randomized controlled trail (RCT) is usually considered the gold standard for 
a clinical trial and it is able to provide the highest level of evidence within all the study 
designs (Howick et al. 2011). RCT can be used to test the efficacy or effectiveness of 
various types of medical/dental intervention. It is the most appropriate study design 
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2. 
HYPOTHESIS AND OBJECTIVES 
2.1. 
Hypothesis 
The hypothesis is that ridge dimensional reductions in the sites of immediate 
implant combined with autogenous tissue graft/acelluar dermal matrix are significantly 
less than the sites of immediate implant alone. Soft tissue augmentation is able to 
increase gingival thickness and limit resorption of bone by expanding the dimension 
of peri-implant mucosa. In addition to limited changes of ridge dimension and 
increased gingival thickness, stable gingival level and increased width of keratinized 
gingiva could also be found following soft tissue augmentation. 
Placement of acellular dermal matrix has comparable clinical outcomes to 
placement of autogenous tissue graft because the clinical trials of mucogingival 
surgery, such as root coverage, show acelluar dermal matrix is as effective as 
autogenous tissue graft. 
2.2. 
Primary Objectives 
This randomized controlled trial aims to evaluate the esthetic outcomes following 
immediate implant combined with the autogenous tissue graft or acellular dermal 
matrix compared to immediate implant alone. Changes of ridge dimension, gingival 
level, gingival thickness, and width of keratinized tissue will be assessed. 
2.3. 
Secondary Objectives 
In addition to the esthetics-related clinical outcomes, the change of bony structure 
will also be measured. The alteration of bony structure around an implant is an 
important clinical parameter indicating the long term stability of the implant. The 
radiographic change of alveolar bone level will be measured on the images of 
periapical radiograph. The change of bone dimension will be measured on the 
images of cone beam computed tomography (CT) 
. 
2.4. 
Potential Risks and Benefits: 
a. 
End Points - Efficacy 
All eligible patients have an unrestorable tooth planned for single implant 
placement. Therefore, all patients in different groups will at least receive the 
appropriate treatments. The patients will not have additional clinical benefits by 
participating in this clinical study, but the patients will have discounted treatments 
(extraction, implant placement, soft tissue augmentation, radiographic examination). 
b. 
End Points - Safety 
1) Study related risks: 
Initial infection, pain or esthetically adverse outcome related to implant placement; 
inability to stabilize the implant due to poor quality of bone; implant failure and need 
for removal; discomfort in function and/or lack of satisfaction with the restoration for 
other reasons. If the implant has to be removed due to severe symptoms and 
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study and receive appropriate treatments. The patients will have the same risks if 
they receive the same treatment without participating in the study. 
2) Protection against risks: 
All efforts will be made to minimize risks to all and every participant: only sites with 
healthy or almost healthy bone levels will qualify for the study to avert esthetic 
concerns, restorative and functional expectations will be discussed and explained. 
3. 
STUDY POPULATION 
3.1. 
List the number of subjects to be enrolled. 
The primary outcome is ridge dimensional alteration at six months after surgery 
while the secondary outcomes are changes of gingival level, gingival thickness, width 
of keratinized gingiva, alveolar bone level and bone dimension. Based on the 
preliminary results, 11 subjects per group need to be recruited to have 80% power to 
detect a 1 mm difference with 0.85 mm standard deviation in ridge dimensional 
change between groups. We plan to enroll 14 subjects in each group to account for 
potential dropout. The subjects will be recruited from the patients enrolled in the 
clinics of University of Texas Health Science Center at Houston School of Dentistry 
(UTSD) and Periodontal and Implant Surgeons of Houston (PISH). There will be no 
restriction on gender or race. 
3.2. 
Criteria for Recruitment 
The study aims to recruit patients enrolled in the clinics of UTSD and PISH. 
Therefore, all the patients will have basic dental examinations following the UTSD 
policy and PISH policy. The clinicians and dental students will be told the information 
of the study and they will be able to preliminarily screen the potential subjects based 
on the selection criteria. If the patients are potentially eligible and interested in 
participating the study, patients will be screened by one of the investigators (Chun- 
Teh Lee, Robin Weltman, Pedro Trejo); only these investigators will be obtaining the 
informed consent form. If additional investigators will be included in the study, we will 
apply for an IRB modification prior to their participation in the study. The qualified 
subjects will be asked to sign the informed consent form and attend the necessary 
appointments of the study. 
3.3. 
Inclusion Criteria 
Forty two subjects will be recruited among the patients attending the Clinic for 
Graduate Periodontics, UTSD, and the Clinic of PISH, who are in need of a tooth 
extraction at the maxillary premolar, canine and incisor region, and subsequent single 
implant placement. The reasons for extraction will include poor endodontic prognosis 
and/or unrestorable teeth (extensive caries, traumatic fractures, fractures of 
endodontically treated teeth, root perforation, root resorption with or without 
radiographic periapical lesion up to 3 mm in diameter). All subjects are ≥18 year-old 
and systemically healthy or with controlled common systemic conditions (controlled 
hypertension, controlled diabetes HbA1c up to 7 %). The adjacent teeth have to be 
present and the eligible tooth has esthetically acceptable buccal gingival margin 
position prior to surgery, compared to neighboring teeth and contralateral tooth, and 
adequate width of buccal keratinized gingiva(≥3mm). The level of radiographic bone 
 

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level has the distance from CEJ to interproximal crest up to 4 mm. 
Location of buccal alveolar crest has to be generally within 4 mm from the free 
gingival margin, verified after the extraction, before randomization; and fenestration, if 
present, up to 3mm in diameter at the apical part of the root and affecting less than 
30% of the buccal socket wall. 
3.4. 
Exclusion Criteria 
Patients will be excluded if they currently smoke exceeding 10 cigarettes/ day, 
have severe parafunctional habits, malocclusion or intent of orthodontic therapy in the 
future and are pregnant. The teeth in the surgical site will be excluded if there is 
advanced periodontal disease or periapical lesion causing significant bony defects 
that are beyond the criteria mentioned at Section 3.3. The patient who is allergy to 
antibiotics contained in the ADM (Gentimicin, Cefoxitin, Lincomcin, polymixin B and 
Vancomycin) will not be included in the immediate implant combined with ADM 
group. 
3.5. 
Withdrawal Criteria 
A subject may be discontinued from participation in the study for any of the 
following reasons: 
1. Withdrawal of consent 
2. Subject noncompliance with the protocol, as determined by the investigator 
3. Any event or condition that would make continued participation in the study not in 
the best interest of the subject, as determined by the investigator 
4. Pregnancy 
5. Development of any medical condition that might affect the treatment and clinical 
outcomes, as determined by the investigator. 
6. Initiation of any treatment or exposure that might affect the outcomes of implant 
therapy, as determined by the investigator. 
7. Investigator discretion 
3.6. 
Subject Replacement 
Subjects who withdraw from the study can be replaced. However, to complete the 
study within the time allocated, centers will not enroll subjects after 24 months from 
enrollment initiation. 
4. 
TRIAL SCHEDULE 
There will be eight appointments including the baseline appointment and seven 
follow-up appointments (2, 4, 8, 12, 24, 36, 48 weeks) after the surgery. The details 
of each visit will be mentioned in 6.3. Study Visits and Procedures. 
5. 
STUDY DESIGN 

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5.1. 
Summary of Study Design 
We propose to conduct a randomized controlled trial with three treatment arms: 
immediate implant, immediate implant combined with SCTG, and immediate implant 
combined with ADM. Patients (age≥18 year-old) need to have single maxillary 
unrestorable tooth which is planned to be replaced with an implant in the esthetic 
zone (maxillary premolar to premolar). The unrestorable tooth has adjacent teeth and 
acceptable periodontal condition (probing depth ≤4mm, gingival recession≤ 1mm at 
six sites: mesial-buccal, mid-buccal, distal-buccal, distal-palatal, mid-palatal, distal- 
palatal). The patients have to be systemically healthy or have controlled common 
systemic conditions (controlled hypertension, controlled diabetes HbA1c up to 7 %). 
Smokers having cigarettes ≤ 10/per day are eligible but they are encouraged to stop 
smoking 1 week prior to and up to 2 months after implant placement (Bain, 1996). 
The primary outcome of the study is the ridge dimensional alterations at six months 
and 12 months after surgery while the secondary outcomes are the changes of 
gingival level, gingival thickness, width of keratinized gingiva, alveolar bone level, and 
bone dimension. 
6. 
METHODS AND ASSESSMENTS 
6.1. 
Randomization and Blinding 
Patient allocation to the three groups (immediate implant combined with SCTG, 
immediate implant combined with ADM, immediate implant alone) was performed by 
a blinded non-surgeon following tooth extraction, based on computer-generated 
randomization (MATLAB). The surgeon will be noticed the randomization results the 
date of performing surgery. Patients will not be blinded given the patients definitely 
know the treatments that they receive due to the characteristics of procedures. 
6.2. 
Contraception and Pregnancy Testing 
Pregnancy status of subjects who are women with childbearing potential will be 
orally confirmed at the screening. The pregnant subjects will be excluded from the 
study. 
6.3. 
Study Visits and Procedures 
. 
a. Screening Visits and Procedures 
Study protocol and consent forms will be approved by the Institutional Review 
Board at the University of Texas Health Science Center at Houston. The trial will be 
registered with ClinicalTrials.gov. The clinicians and dental students in UTSD and 
PISH will be told the information of this clinical trial. The potential subjects who are 
interested in participating in this project will be referred to the clinic of Department of 
Periodontics and Dental Hygiene, UTSD or the clinic of PISH for initial screening. The 
principal investigator will confirm the eligibility of these patients. All patients will have 
dental cone-beam computed tomography before the surgery given the implants will 
 

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be placed in the highly esthetic zone (Benavides et al. 2012). All patients will sign the 
consent forms and are informed of the details of study procedures as well as potential 
complications. After informed consent is obtained, and initial periodontal therapy and 
oral hygiene instruction, whenever indicated, the surgery will be scheduled as the first 
visit. 
At the first appointment, all clinical measurements will be performed (probing 
depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), plaque index 
(PI)) and the impression of maxillary and mandibular dentition will be taken. One 
periapical radiography of the surgical site will be taken after the surgery is finished. 
After verification that the local anatomical inclusion criteria are met, patients will be 
randomized to one of three treatment groups. All implants will be placed according to 
standard protocol at a subcrestal position (1 mm below the buccal crest) engaging 
the palatal wall without elevation of a mucoperiosteal flap. The gap between the 
implant and alveolar bone will be filled with xenograft (Geistlich Bio-Oss®) and 
covered by collagen dressing (CollaTape®). In the groups having soft tissue 
augmentation, intrasulcular incisions will be carried out to partially dissect the buccal 
flap from mesial papilla to distal papilla. The SCTG or ADM will be inserted into the 
dissected buccal flap. The SCTG will be subepithelially harvested from the palate of 
the patient. The width of tissue graft will be equal to the distance between the 
interproximal papillae on the level of buccal gingival margin. The length of SCTG will 
be standardized as 10 mm. The thickness of SCTG will be standardized as 1-1.5mm. 
The size of ADM will be standardized following the same principle. The SCTG tissue 
graft or ADM will be stabilized by sling suture (chromic gut 5-0). 
In the three groups, the straight healing abutment will be delivered immediately 
after implant placement provided that the implant shows primary stability and has 
engaged in the bone with an insertion torque of 25 Ncm or more (Norton 2004). In 
case of a lower insertion torque, the protocol will be abandoned, a cover screw will be 
placed, and a two stage implant protocol will be followed. All patients will receive a 
permanent restoration at 6 months after surgery, if the implant is deemed to be 
successful (Misch et al. 2008). The placement of xenografts aims to optimize the 
esthetic outcomes. 
All patients will receive Amoxicillin 500mg, t.i.d, (for penicillin allergic patients: 
Clindamycin 150 mg, q.i.d) for seven days following surgery. Patients will be 
instructed to use mouth rinse (Chlorhexidine 0.12%) twice daily during the first two 
weeks and avoid brushing the surgical area for two weeks. All patients will be seen 
at two weeks following surgery, remove suture, follow up of healing, and oral hygiene; 
at 4 weeks (supragingival prophylaxis) ; at 8 weeks (supragingival prophylaxis); at 3 
months (prophylaxis and measurements); at 6 months (prophylaxis, measurements, 
periapical radiography, cone beam computed tomography, impression for the 
permanent restoration). The permanent restoration will be delivered within one month 
following the final impression taken. After the crown placement, the patients will be 
seen at 9 months (prophylaxis) and 12 months (prophylaxis, measurements, 
periapical radiography, impression). 
. 
b. Study Visits and Procedures 
A stent with reference notches made by #1/2 bur at a 2 mm distance from the 
gingival margin at the mesio-buccal, mid-buccal and disto-buccal sites will be 
fabricated. The stent will be made based on the patient’s dental model to have the 
best fit. A new stent with the same design will be made after patients have permanent 
restorations and the stent will be used to measure the parameter at the 12-month 
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The following measurements will be carried out at the visits: 
1) Soft tissue distance from each of the three notches (mesio-buccally, mid-buccally 
and disto-buccally, respectively): the distance is measured from the notch to the 
gingival margin at three sites; it is measured at implant placement visit (baseline), 3 
months, 6 months, and 12 months. 
2) Horizontal defect dimension (HDD) defined as horizontal distance from the implant 
shoulder to the buccal alveolar socket wall, measured in the mid-buccal site; it is 
measured only at implant placement visit (the first visit). 
3) Vertical defect dimension (VDD) defined as vertical distance from implant shoulder 
to the apical contact with the socket wall, measured in the mid-buccal site; it is 
measured only at implant placement visit (the first visit). 
4) Buccal soft tissue thickness will be measured following the extraction using the 
endodontic file and the digital caliper (one measurement/ mid-buccal/6mm apical to 
gingival margin); it is measured before and after implant surgery at the first visit, 6 
months and 12 months. 
5) Probing depth (PD): probing depth is defined as the distance from the gingival 
margin to the tip point of the probe (Williams probe). PDs will be measured at 6 sites 
per tooth (mesio-buccal, mid-buccal, disto-buccal, disto-palatal, mid-palatal, mesio- 
palatal); it is measured before surgery at the first visit, 3 months, 6 months and 12 
months. 
6) Bleeding on probing (BOP): the prevalence of bleeding on probing at six sites 
(mesio-buccal, mid-buccal, disto-buccal, disto-palatal, mid-palatal, mesio-palatal) of 
the tooth/implant will be documented at the first visit, 3 months, 6 months and 12 
months. 
7) Plaque index (PI): A periodontal probe will be swept along each site to all the teeth 
to identify the presence or absence of plaque accumulation at the first visit, 3 months, 
6 months and 12 months. A dichotomous scoring system will be used with one (1) 
and zero (0) equaling presence and absence, respectively, of plaque. 
8) Buccal-palatal dimension of the ridge at the site of implant placement: the 
dimension will be measured at different reference points (3 mm, 6 mm from the 
baseline gingival margin) on the study model. Impressions for study models will be 
taken at the first visit, at 3 months, 6 months and 12 months. The measurement will 
be done by the digital caliper and the computer assisted scanned images. 
9) Buccal plate thickness: it will be measured on the images of dental cone beam 
computed tomography. The patients will have the images taken with a stent before 
the surgery and 6 months after the surgery. The stent will be made based on the 
patient’s dental model. The midline of the implant site will be buccally and palatally 
marked with gutta percha. 
10) Interproximal bone level: a film holder with silicon putty to aid in reproducibility of 
the radiograph position will be used. The mesial and distal crestal bone level will be 
measured using the MIPACS software. Implant platform will serve as the reference 
point. Vertical and horizontal changes (depth and width of the vertical defect on the 
mesial and/or distal aspect of the implant, if present) will also be measured from 
radiographs taken at the time of completion of surgery, at 6 and 12 months. Dose and 
frequency of x-rays in the study are standard of care for any implant patient in UTSD, 
PISH or in standard clinical practice, and are not altered for the purpose of the study. 
(Medical status is updated and recorded at each visit, including verification that 
female patients are not pregnant prior to x-ray taking; this is also standard of care). 
11) The diameter of the apical radiolucency, when initially present, will be monitored 
radiographically. Any lesions present in the radiography will be assessed immediately 
after surgery and 6 months. 
12) Blood flow of gingiva: The laser Doppler flowmeter is a noninvasive measure 
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surface of buccal gingival. It is measured before and after implant surgery at the first 
visit, 3 months, 6 months and 12 months. 
c. Final Study Visit: 
The 12-month follow-up will be the subject’s last visit for this clinical trial. 
The patients will have clinical measurements (PD, BOP, PI), dental impressions 
taken, and periapical radiographic examination. All subjects will have periodontal 
maintenance in the periodontics clinic of UTSD or PISH in the future. 
d. Post Study Follow up and Procedures 
The subjects will continue having routine maintenance appointments to follow up 
the health and function of implants and teeth in the periodontics clinic of UTSD or 
PISH. If the patients have symptoms of inflammation and signs of progression bone 
loss, the necessary treatments, such as debridement, will be performed. 
e. Discontinuation Visit and Procedures 
Subjects are free to withdraw from participation in the study at any time upon 
request. A subject may be discontinued from participation in the study for any of the 
following reasons: 
1. Withdrawal of consent 
2. Subject noncompliance with the protocol, as determined by the investigator 
3. Any event or condition that would make continued participation in the study not in 
the best interest of the subject, as determined by the investigator 
4. Pregnancy 
5. Development of any medical condition that might affect the treatment and clinical 
outcomes, as determined by the investigator. 
6. Initiation of any treatment or exposure that might affect the outcomes of implant 
therapy, as determined by the investigator. 
7. Investigator discretion 
Any subject with a serious adverse event, such as life-threating diseases, 
hospitalization, that is ongoing at the time of discontinuation will be followed until the 
event returns to baseline, resolves, or stabilizes. If the serious adverse event does 
not meet these outcomes within 30 days after discontinuation or after study 
completion, the subject will be referred to an appropriate practitioner for continued 
care. If the study is discontinued, subjects will be referred back to the qualified 
clinicians for necessary dental care. 
7. 
TRIAL MATERIALS 
. 
7.1. 
Trial Product (s) 
Implants, bone grafts (Bio-Oss) and collagen dressing (CollaTape®) will be used 
following the indications approved by Food and Drug Administration (FDA). Implants 
will be placed to support the crowns to restore patients’ oral esthetics and functions. 
Bone grafts are placed to preserve the socket dimension following extraction. 
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AlloDerm® Regenerative Tissue Matrix (RTM) is the one of the most widely used 
substitutes for autogeneous tissue graft in dentistry. It is an acellular dermal matrix 
(ADM) that is derived from donated human skin and is minimally processed to 
remove epidermal and dermal cells with nondenaturing detergent while preserving 
the extracellular matrix. The removal of viable cells and antigens during the 
decellularization process minimizes the risk of rejection and inflammation at the 
surgical site. Then, a cyropreservant is added to avoid crystal formation, and then 
resulting tissue matrix is freeze-dried(Wang et al. 2015). The remaining matrix serves 
as a framework for cellular infiltration and vascularization. ADM is indicated for soft 
tissue augmentation (Batista et al. 2001; Griffin et al. 2004; Park and Wang 2006), 
gingival recession defect coverage (Andrade et al. 2008; Tal et al. 2002), keratinized 
gingiva extension (Harris 2001; Yan et al. 2006), and extraction socket coverage 
(Fowler et al. 2000; Froum et al. 2004; Park 2011) for both teeth and implants. 
Basically, ADM can be used in all the procedures that the autogenous tissue graft is 
indicated for. 
. 
7.2. 
Storage and Drug Accountability 
Implants, bone grafts, collage dressing, and AlloDerm® Regenerative Tissue 
Matrix will be stored at room temperature in its original packaging following the 
manual instruction. The expiration date for the product is recorded on the product 
container labeling as year (4 digits) and month (2 digits) and the product expires on 
the last day of the month indicated. Expiration date printed on the labeling is valid as 
long as product is stored at room temperature and in an unopened foil 
pouch/packaging. Once the product is expired, the material will be discarded. 
8. 
TREATMENT 
8.1. 
Rationale for Selection of Treatments 
Although subjects will be assigned to different experimental groups, all treatments are 
conducted following general clinical principles. The details of procedure are 
mentioned in section 6.3. 
8.2. 
Specific Restrictions / Requirements 
Subjects will be instructed to discontinue brushing the surgical area, to use mouth 
rinse (Chlorhexidine 0.12%) twice daily during the first two weeks and to avoid biting 
at the surgical area for at least two months. 
8.3. 
Blinding 
The surgeons and patients cannot be blinded because the surgeons will be told 
which procedure to perform at the first visit and patients will be aware of the 
procedures that they received after surgery. The patients will be informed of benefits 
of all the procedures and realize all procedures are supported by scientific evidence. 

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9. 
SAFETY MEASUREMENTS 
9.1. 
Definitions 
All unanticipated problems will be reported in this study. The Committee For the 
Protection of Human Subjects (CPHS) considers unanticipated problems to be any 
incident, experience, or outcome that meets all of the following criteria: 
Is unexpected in terms of nature, severity, or frequency given a) the research 
procedures that are described in the IRB-approved research protocol and informed 
consent, and b) the characteristics of the subject population being studied; 
Is related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcome may 
have been caused by the procedures involved in the research); and 
Places subjects or others at a greater risk for physical, psychological, economic, or 
social harm than was previously known or recognized. 
An incident, experience, or outcome that meets the 3 criteria above will generally 
warrant consideration of substantive changes in order to protect the safety, welfare, 
or rights of subjects or others. Examples of corrective actions or substantive changes 
that might need to be considered in response to an unanticipated problem include the 
following: 
Changes to the research protocol initiated by the investigator prior to obtaining IRB 
approval to eliminate apparent immediate hazards to subjects 
Modification of inclusion or exclusion criteria to mitigate newly identified risks 
Implementation of additional procedures for monitoring subjects 
Suspension of enrollment of new subjects 
Suspension of research procedures in currently enrolled subjects 
For this study, an severe adverse event (SAE) is defined as an unanticipated 
problem occurring during the study that fulfils 1 or more of the following criteria: 
1. Results in death 
2. Is immediately life-threatening† 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
4. Results in persistent or significant disability or incapacity 
5. Is a congenital abnormality or birth defect 
6. Is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above 
Hospitalization for elective procedures or surgeries will not be considered SAEs, 
nor will inpatient hospitalizations for convenience. 
Pregnancy in women with childbearing potential should not be reported as an 
SAE, but if pregnancy occurs, it must be reported in accordance with the procedures 
described in Section 6.2. Pregnancy will not be regarded as an SAE unless there is 
suspicion that a study intervention may have interfered with the effectiveness of a 
contraceptive medication and the event meets the criteria for an unanticipated 
problem. If the pregnancy results in an outcome other than a normal birth or elective 
abortion of a healthy fetus, it will be reported as an SAE. 
9.2. 
Collecting, Recording and Reporting of Adverse Events 
Examination and close follow-up of parameters capturing subjects’ oral health will 
be collected on case report forms (CRFs). These will be completed at every study 
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the PI for safety oversight. 
Serious adverse events (as defined in Section 9.1) will be collected from the time 
of enrollment until the last clinic visit and will be recorded in the electronic health 
records (EHR) system. At each study visit, the study staff will inquire about the 
occurrence of SAEs since the last assessment. The investigator will review all source 
documentation related to study procedures for evidence of SAEs. Events will be 
followed for outcome information until they return to baseline or stabilize, or until 30 
days after study completion or subject discontinuation. Subjects who have an SAE 
that is ongoing 30 days after study completion or discontinuation will be referred to an 
appropriate practitioner for continued care. 
Upon learning that a subject has experienced an SAE, the investigator must report 
the event to CPHS within 24 hours after becoming aware of the event. 
On a monthly basis, the following events will be reported to every PI: 
Number of subjects meeting criteria for implant failure and number of subjects 
enrolled. 
Duration of observation of subjects meeting implant failure criteria and duration of 
observation of subjects enrolled 
For subjects having failed implants: 
• 
Criteria for failure implants 
• 
Baseline enrollment and interim visit information 
Any tooth loss, abscess, or other adverse oral health development requiring 
therapy or other intervention and the etiology (as captured in the dental history) 
Every PI will review the monthly reports for any safety signals. 
9.3. 
Safety Monitoring Plan 
The purposes of the clinical monitoring activities are to ensure that the rights of 
human subjects are protected, the study is implemented in accordance with the 
protocol, and the integrity of study data is maintained. 
All subjects will be monitored for postoperative healing and tissue response at a 
regular interval while the entire oral health will be maintained throughout the study 
period. 
10. 
DATA ANALYSIS 
10.1. Data Quality Assurance 
Data and measurements will be checked by two separate sub-investigators (Chun- 
Teh Lee, Robin Weltman) as well as analyzed statistically to ensure that the data 
obtained is accurate, complete and reliable. 
10.2. Data Entry and Storage 
Case report forms (CRFs) will be completed and stored in a locked file cabinet in the 
PI’s office located at UTSD. Data will be entered electronically in excel spreadsheets, 
and images will be stored electronically; both will be stored on the PIs work computer 
in a locked office and password protected. 
 

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11. 
SAMPLE SIZE AND STATISTICAL METHODS 
11.1. Determination of Sample Size 
Hypothesis: 
H1: Ridge dimensional reductions in the sites of immediate implant combined with 
autogenous tissue graft/acelluar dermal matrix are significantly less than the sites of 
immediate implant alone. 
Null hypothesis: 
H0: Ridge dimensional reductions in the sites of immediate implant combined with 
autogenous tissue graft/acelluar dermal matrix are not significantly less than the sites 
of immediate implant alone. 
Significance Tests: 
If significance tests generate 95% likelihood that the results do not fit the null 
hypothesis (H0), then it is rejected, in favour of the alternative (H1). 
Otherwise, the null is accepted. These are the only correct assumptions, and it is 
incorrect to reject, or accept, H1. 
Accepting the null hypothesis does not mean that it is true. It is still a hypothesis, and 
must conform to the principle of falsifiability, in the same way that rejecting the null 
does not prove the alternative. 
Calculation of Sample Size: 
Based on the data published in the articles and preliminary results, we have 
calculated that 11 subjects per group need to be recruited in order to have 80% 
power to detect a 1mm difference with 0.9 mm standard deviation in ridge 
dimensional change between the immediate implant alone group and the other two 
groups (Faul et al. 2009). We plan to enroll a total of 42 subjects (14 subjects in each 
group) to account for potential dropout. 
11.2. Statistical and Analytical Plans 
a. General Considerations 
We will present means and standard deviations for completeness of the report. The 
statistical significance level to test the primary endpoint was set at p<0.05, a priori. 
b. Safety Analyses 
Safety will be evaluated by tabulations of adverse events and will be presented with 
descriptive statistics at Baseline and follow-up visits each month. 
Adverse events will be classified as biological complications, such as severe 
inflammation, progressive alveolar bone loss>2mm, or prosthetic complications, such 
as lose of healing abutment and summarized for both baseline and follow-up visits. 
All information pertaining to adverse events noted during the study will be listed by 

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subject, detailing verbatim given by the investigator, preferred term, , date of onset, 
date of resolution, severity, and relationship to procedure. The onset of adverse 
events will also be shown relative (in number of days) to the day of performing the 
surgery. 
A tabulation of Serious Adverse Events (SAEs) will be provided by subject within 
treatment groups. The proportion of subjects in each treatment group reporting 
adverse events that occur in ~ 3% in either treatment group will be compared using 
Bayesian methods. The specific preferred terms analysed will be those that are 
reported by at least five percent of the subjects in either treatment group. 
c. Statistical Analysis Plan: 
Differences in the primary and secondary outcomes between the three groups will be 
examined using the one-way ANOVA analysis. Differences in the primary and 
secondary outcomes overtime within each group will be examined using paired t-test. 
The level of significance will be set at 0.05 and Bonferroni corrections for multiple 
comparisons will be carried out. All statistical analysis will be performed using SAS 
version 9.4 (SAS Institute, Cary NC). The data derived from withdrawn patients will 
be included in the analysis. 
12. 
ETHICAL CONSIDERATIONS 
12.1. Informed Consent 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Extensive discussion of risks and possible benefits of study participation will be 
provided to the subjects and their families. A consent form describing in detail the 
study interventions, procedures, and risks will be given to the subject. Consent forms 
will be IRB-approved, and the subject will be asked to read and review the document. 
The investigator or designee will explain the research study to the subject and 
answer any questions that may arise. The subject will sign the informed consent 
document prior to any study-related assessments or procedures. Subjects will be 
given the opportunity to discuss the study with their surrogates or think about it prior 
to agreeing to participate. They may withdraw consent at any time throughout the 
course of the trial. A copy of the signed informed consent document will be given to 
subjects for their records. The rights and welfare of the subjects will be protected by 
emphasizing to them that the quality of their clinical care will not be adversely 
affected if they decline to participate in this study. 
The consent process will be documented in the clinical or research record. This 
documentation will include the following: 
A notation of the date that the consent was obtained 
A statement that the consent was obtained prior to the initiation of study 
procedures 
A statement that the subject had adequate time to review the consent and that all 
questions were answered prior to initiation of study procedures 
A notation confirming that a copy of the signed consent was given to the subject 
 

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12.2. IRB review 
The protocol, informed consent form(s), and all advertising and subject materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and 
informed consent form must be obtained before the enrollment of any subject. Any 
amendment to the protocol will require review and approval by the IRB before the 
changes are implemented in the clinic. 
12.3. Confidentiality of Data and Patient Records 
The subject’s name will appear only on the consent form and clinical record, both of 
which will be kept separate from collected study data. All subject files will be kept 
confidential and placed in a double-locked office. A unique coded study number will 
be assigned to each subject for data collection. The number will not contain any 
personal information (e.g., dates, age) to further ensure protection. 
The study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be 
released to any unauthorized third party without prior written approval of the PI. No 
subject names will be used in publications or presentations. 
13. 
PUBLICATIONS 
Following completion of the study, the investigator is expected to publish the results 
of this research in a scientific journal. The International Committee of Medical Journal 
Editors (ICMJE) member journals have adopted a trials-registration policy as a 
condition for publication. This policy requires that all clinical trials be registered in a 
public trials registry such as ClinicalTrials.gov (De Angelis et al. 2004), which is 
sponsored by the National Library of Medicine. Other biomedical journals are 
considering adopting similar policies. For grants and cooperative agreements, it is 
the institution’s responsibility to register the trial in an acceptable registry. 
The ICMJE defines a clinical trial as any research project that prospectively assigns 
human subjects to intervention or comparison groups to study the cause-and-effect 
relationship between a medical intervention and a health outcome. Studies designed 
for other purposes, such as to study pharmacokinetics or major toxicity (e.g., phase I 
trials), would be exempt from registering trials in a public registry such as 
ClinicalTrials.gov. 
14. 
RETENTION OF TRIAL DOCUMENTS 
Patients will be assigned identifying codes that will be linked to all collected study 
data, stored in secured database by Primary Investigator. All the electronic files will 
be encrypted and are stored in primary investigator's external drive, that will be 
locked in the PI's office cabinet. Models will be stored in a locked cabinet in the PI's 
office. The following individuals/ institutions will have access to the records: the 
Principal Investigator and coinvestigators, and the University of Texas Health Science 
Center at Houston, including the Institutional Review Board. Absolute confidentiality 
cannot be guaranteed because of potential need to share this information with the 
above parties. The aggregate results of this study, with preservation of patient 
confidentiality, may be used for teaching, meeting presentation or publishing purpose. 
Records will be maintained for at least 6 years from the starting date of each subject. 

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List of Possible Attachments 
 
Appendix 1 
Case report form 
Appendix 2 
Flyer 
Appendix 3 
Informed Consent Form 
Appendix 4 
Schematic of Study Design 
Appendix 5 
Study Schedule 
Appendix 6 
Screening examination checklist 
 
 
 
 
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