3D Printed Scaffold Device for Ridge Preservation After Tooth Extraction - A Randomised Controlled Clinical Trial
Phase: NA
Conditions: Bone Resorption After Tooth Extraction
Sponsor: National Dental Centre, Singapore

Version <No.2>, Dated <15/03/2018> 
Page 1 of 26 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
PROTOCOL TITLE: 
3D Printed Scaffold Device for Ridge Preservation after Tooth Extraction – A Randomised Controlled 
Clinical Trial 
 
PROTOCOL NUMBER:  
252/2017 
 
PROTOCOL VERSION:  
2 
PROTOCOL DATE:  
15 March 2018 
 
PRINCIPAL INVESTIGATOR:  
Dr Goh Bee Tin, Senior Consultant, NDCS 
 
 
CO-INVESTIGATORS: 
Dr Nattharee Chanchareonsook, Consultant, NDCS 
Dr Edwin Liu, Senior Research Manager, NDCS 
Dr Lim Jing, Product Development Manager, Osteopore International (Singapore) 
Adjunct A/Prof Goh Khoon Seng, CEO, Osteopore International (Singapore) 
Prof Teoh Swee Hin, School of Chemical and Biomedical Engineering, Nanyang Technological University 
 
 
 
 
 
 
 
 
 

Version <No.2>, Dated <15/03/2018> 
Page 2 of 26 
Table of Contents 
      
LIST OF ACRONYMS ........................................................................................................................... 4 
1 
BACKGROUND AND RATIONALE................................................................................................. 7 
1.1 
GENERAL INTRODUCTION ................................................................................................................... 8 
1.2 
RATIONALE AND JUSTIFICATION FOR THE STUDY .................................................................................... 10 
1.2.1 
RATIONALE FOR THE STUDY PURPOSE ................................................................................................. 10 
1.2.2 
RATIONALE FOR STUDY POPULATION .................................................................................................. 11 
1.2.3 
RATIONALE FOR STUDY DESIGN ......................................................................................................... 12 
2 
HYPOTHESIS AND OBJECTIVES ............................................................................................... 12 
2.1 
HYPOTHESIS ................................................................................................................................. 12 
2.2 
PRIMARY OBJECTIVES ..................................................................................................................... 12 
2.3 
SECONDARY OBJECTIVES ................................................................................................................. 12 
2.4 
POTENTIAL RISKS AND BENEFITS: ...................................................................................................... 13 
2.4.1 
POTENTIAL RISKS .......................................................................................................................... 13 
2.4.2 
POTENTIAL BENEFITS ...................................................................................................................... 13 
3 
STUDY POPULATION ................................................................................................................ 13 
3.1 
LIST THE NUMBER AND NATURE OF PATIENTS TO BE ENROLLED. ................................................................ 13 
3.2 
CRITERIA FOR RECRUITMENT AND RECRUITMENT PROCESS ....................................................................... 14 
3.3 
INCLUSION CRITERIA ...................................................................................................................... 14 
3.4 
EXCLUSION CRITERIA ...................................................................................................................... 14 
4 
STUDY DESIGN ......................................................................................................................... 14 
4.1 
RANDOMISATION AND BLINDING ........................................................................................................ 17 
4.2 
CONTRACEPTION AND PREGNANCY TESTING .......................................................................................... 17 
4.3 
STUDY VISITS AND PROCEDURES ....................................................................................................... 17 
4.3.1 
SCREENING VISITS AND PROCEDURES ................................................................................................. 17 
4.3.2 
STUDY VISITS AND PROCEDURES ....................................................................................................... 18 
4.3.3 
FINAL STUDY VISIT: ....................................................................................................................... 19 
4.3.4 
POST STUDY FOLLOW UP AND PROCEDURES .......................................................................................... 19 
4.4 
DISCONTINUATION/WITHDRAWAL ...................................................................................................... 20 
4.4.1 
DISCONTINUATION CRITERIA ............................................................................................................ 20 
4.4.2 
DISCONTINUATION VISIT AND PROCEDURES ......................................................................................... 20 
5 
TRIAL MATERIALS .................................................................................................................... 20 
5.1 
TRIAL PRODUCT (S) ....................................................................................................................... 20 
5.2 
STORAGE AND DRUG ACCOUNTABILITY ................................................................................................ 21 
6 
TREATMENT .............................................................................................................................. 21 
6.1 
RATIONALE FOR SELECTION OF DOSE .................................................................................................. 21 
6.2 
STUDY DRUG FORMULATIONS ........................................................................................................... 21 
6.3 
STUDY DRUG ADMINISTRATION ......................................................................................................... 21 
6.4 
SPECIFIC RESTRICTIONS / REQUIREMENTS ........................................................................................... 21 
6.5 
BLINDING .................................................................................................................................... 21 
6.6 
CONCOMITANT THERAPY .................................................................................................................. 21 
7 
SAFETY MEASUREMENTS.......................................................................................................... 22 
7.1 
DEFINITIONS ................................................................................................................................ 22 
7.2 
COLLECTING, RECORDING AND REPORTING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS TO CIRB .......... 22 

Version <No.2>, Dated <15/03/2018> 
Page 3 of 26 
7.3 
COLLECTING, RECORDING AND REPORTING OF SERIOUS ADVERSE EVENTS (SAES) TO THE HEALTH SCIENCE 
AUTHORITY (HSA) .................................................................................................................................... 23 
7.4 
SAFETY MONITORING PLAN .............................................................................................................. 23 
7.5 
COMPLAINT HANDLING .................................................................................................................... 23 
8 
DATA ANALYSIS........................................................................................................................ 23 
8.1 
DATA QUALITY ASSURANCE .............................................................................................................. 23 
8.2 
DATA ENTRY AND STORAGE .............................................................................................................. 24 
9 
SAMPLE SIZE AND STATISTICAL METHODS ............................................................................. 24 
9.1 
DETERMINATION OF SAMPLE SIZE ...................................................................................................... 24 
9.2 
STATISTICAL AND ANALYTICAL PLANS ................................................................................................. 24 
10 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................................... 24 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................... 25 
12 
ETHICAL CONSIDERATIONS ..................................................................................................... 25 
12.1 
INFORMED CONSENT....................................................................................................................... 25 
12.2 
CONFIDENTIALITY OF DATA AND PATIENT RECORDS ............................................................................... 25 
13 
PUBLICATIONS ......................................................................................................................... 25 
14 
RETENTION OF TRIAL DOCUMENTS ......................................................................................... 26 
15 
FUNDING AND INSURANCE ...................................................................................................... 26 

Version <No.2>, Dated <15/03/2018> 
Page 4 of 26 
LIST OF ACRONYMS 
 
 
3D – 3 Dimensional  
 
ASA - American Society of Anesthesiologists 
 
AE – Adverse Event 
 
BV – Bone Volume 
 
CIRB – Centralized Institutional Review Board 
 
CRF – Case Report Form 
 
CT - Computed Tomography 
 
DFDBA - Demineralized freeze-dried bone allograft 
 
FDA - Food and Drug Administration 
 
FDM - Fused Deposition Modelling 
 
HSA – Health Science Authority 
 
ISQ - Implant Stability Quotient 
 
NDCS – National Dental Centre Singapore 
 
NTU – Nanyang Technological University 
 
OI – Osteopore International  
 
OPG – Orthopantomogram 
 
PCL TCP - Polycaprolactone – tricalcium phosphate 
 
PCL – Polycaprolactone 
 
RFA – Resonance Frequency Analysis 
 
RHmeb– Ridge height mesio-buccal  
 
RHmib – Ridge height mid-buccal  
 
RHdb – Ridge height disto-buccal  
 
RW – Ridge Width 
 
SAE – Serious Adverse Event 
 
TCP - Tricalcium phosphate 
 
 

Version <No.2>, Dated <15/03/2018> 
Page 5 of 26 
 
 
PROTOCOL SIGNATURE PAGE 
 
 
 
Protocol Title: 3D Printed Scaffold Device for Ridge Preservation after Tooth Extraction – A Randomised 
Controlled Clinical Trial 
 
 
Protocol Number: 252/2017 
 
 
Protocol Version/ Date: Version 2/ 15 March 2018 
 
 
Sponsor Name: Osteopore International (Singapore) Pte Ltd 
 
 
 
Declaration of Investigator 
 
I confirm that I have read the above-mentioned protocol and its attachments. I agree to conduct the 
described trial in compliance with all stipulations of the protocol, regulations and ICH E6 Guideline for 
Good Clinical Practice (GCP) 
 
  
 
 
Principal Investigator Name:  Cl A/Prof Goh Bee Tin 
 
                                                                           
 
Principal Investigator Signature:  _______________________________________ 
                                                            
                                     
 
Date:  __________________________________________ 
                                                            
 
 
 
 
 
 

Version <No.2>, Dated <15/03/2018> 
Page 6 of 26 
 

Version <No.2>, Dated <15/03/2018> 
Page 7 of 26 
1 
BACKGROUND AND RATIONALE 
 
Dental implant-supported prostheses are fast gaining popularity as the treatment of choice for tooth 
replacement. Dental implants and their respective parts and tools have become the fastest growing area in 
dentistry and the dental supply industry. The basis for modern dental implants (endosseous implant) is a 
biologic process called osseointegration, which refers to a direct structural and functional connection 
between ordered, living bone and the surface of a load-carrying implant. The long-term success of dental 
implants, in terms of clinical stability and aesthetic result of the prosthesis, is dependent on the dental 
implant being supported by adequate amount of bone in the alveolar ridge. 
 
Following tooth extraction, the socket usually heals naturally with bone tissue in 1 to 2 months1-3. This 
healing process, however, occurs with substantial reduction of the original height and width of the alveolar 
ridge (Figure 1). Most of the dimensional alterations occur in the first 2 to 3 months after tooth 
extraction4,5. In a systematic review, a reduction of 3.87 mm and 1.67 mm in alveolar bone width and 
height respectively within 3 months after dental extraction was reported6. Another systematic review 
reported vertical dimensional change of 11 - 22 % and a horizontal dimensional change of 29 - 63% in the 
alveolar ridge at 6 months after dental extraction7. Bone resorption is more pronounced on the buccal 
than the palatal/ lingual aspect of the ridge5,8,9. The resultant effect of this resorption pattern is 
transportation of the diminished ridge to a more palatal or lingual position.   
 
 
 
In a significantly resorbed ridge, bone augmentation procedures are necessary before surgical dental 
implant placement. Currently, autogenous bone is considered the gold standard as a graft material for this 
purpose. The bone may be harvested from various locations, such as the mandibular ramus, chin, iliac 
crest or calvarium, depending on, among other factors, the quantity of bone required. This implies that the 
patient is subjected to additional surgery and its associated morbidities and expenses. The cost of 
autogenous bone augmentation surgery ranges from about SGD$1350 (e.g. mandibular or chin donor site) 
to about SGD$8000 (e.g. iliac crest donor site, requiring an average of 4 days hospital stay). Patients 
seeking dental treatment are often expecting simple and less invasive solutions and are often unwilling to 
undergo complicated and expensive surgery.  
 
To counteract alveolar ridge resorption after extraction, “ridge preservation” techniques have been 
introduced9,10. Ridge preservation is defined as any procedure undertaken at the time of or following an 
extraction that is designed to minimise external resorption of the ridge and maximise bone formation 
within the socket11. For this purpose, xenografts, allografts and/ or synthetic materials used alone or in 
conjunction with a membrane have been used to fill the tooth socket. Among the various materials 
available12-18, bovine porous bone mineral12 and demineralised freeze-dried bone allograft (DFDBA)13-15 are 
the most commonly used. While studies have shown these materials to be effective in preserving ridge 
dimensions to some extent19,20, they failed to prevent vertical resorption of the buccal and palatal 
bony walls21. Their osteoconductivity is suboptimal and unpredictable and the graft materials often 
interfered with the normal healing process13-15,22. Sites grafted with a bovine bone mineral Bio-Oss® were 
found to comprise of connective tissue and only 40% of the circumference of the Bio-Oss® particles was 
in contact with woven bone23. Another study using DFDBA showed no evidence of bone formation on 
Figure 1: Bone resorption after tooth 
extraction resulting in reduction in ridge 
height and width 

Version <No.2>, Dated <15/03/2018> 
Page 8 of 26 
the surfaces of the non-viable particles13. Several other investigators have demonstrated the presence of 
graft particles in alveolar sockets for as long as 6 to 9 months following insertion12,15,24,25 and they may not 
be fully replaced by host bone even after a prolonged period of healing. The use of xenografts and 
allografts also subjects the patient to small risks of disease transmission and adverse immune reaction and 
their use may not be acceptable for certain religions or cultures. 
 
Cost of bone substitutes: 
Bone substitute 
Price (SGD) 
Xenograft 
Bio-Oss® 0.25g 
Bio-Oss® 0.50g 
 
$139 
$201 
Allograft 
Puros® 0.5cc 
Puros® 1.0cc 
Puros® 2.0cc 
 
$220 
$303 
$482 
 
Market Size 
Dental implant and bone augmentation surgeries are commonly performed procedures in Singapore and 
globally. The market size and potential for growth are tremendous. According to business report 
provider GBI Research, the global dental implants market is expected to grow at a compound rate of 10 
percent from $3.4 billion in 2011 to $6.6 billion in 2018. The rapid growth is driven by the ageing 
population worldwide as well as technological advancements that have markedly improved dental implant 
treatment efficiency and success rate (Dental Tribune International 11 Feb 2013). According to another 
report from research and consulting firm GlobalData, the global bone grafts and substitutes market value 
will similarly increase steadily over the coming years, rising from almost $2.1 billion in 2013 to 
approximately $2.7 billion by 2020, at a compound rate of 3.8% (GlobalData 29 Jan 2014).  
Unpublished data estimated that 15,000 dental implants are being inserted in patients per year in 
Singapore. 
 
 
1.1 General Introduction 
 
 
To meet the clinical need of maintaining bone volume and contour of the alveolar ridge following tooth 
extraction, we propose the solution of using a novel 3-dimensional (3D) printed polycaprolactone – 
tricalcium phosphate (PCL-TCP) bioresorbable scaffold device for ridge preservation.   
 
Polycaprolactone (PCL) is a bioresorbable polymer and is regarded as a non-toxic and tissue-compatible 
material26. It has been used in many medical devices for the last 30 years such as Capronor™, a one-year 
implantable subdermal contraceptive device27 and Monocryl™ a resorbable monofilament suture28.  Both 
are Food and Drug Administration (FDA)-approved clinical products. More recently it has been approved 
as 
a 
bone 
filler 
for 
craniofacial 
applications 
(510K 
FDA 
K051093) 
(http://www.accessdata.fda.gov/cdrh_docs/pdf5/K051093.pdf). The PCL scaffold is intended for use in 
the repair of neurosurgical burr holes, craniotomy cuts and other cranial defects and in the augmentation 
or restoration of bony contour in the craniofacial skeleton29. An interdisciplinary group, then at the 
National University of Singapore led by Prof Teoh Swee Hin, in collaboration with Temasek Polytechnic, 
evaluated and patented the parameters used to process PCL and PCL composites by an Additive 
Manufacturing or 3D printing technique known as Fused Deposition Modelling (FDM)30. The unique 
feature of these FDM scaffolds lies in the 3-angle layering (0°/60°/120°) that results in a fully 

Version <No.2>, Dated <15/03/2018> 
Page 9 of 26 
interconnected matrix architecture that provides maximum anchorage for cell attachment30-32. The scaffold 
has mechanical properties closely similar to bone, exhibits slow degradation kinetics, enhances blood clot 
entrapment and vascular ingrowth and is osteoconductive. PCL products manufactured and 
commercialized by Osteopore International (OI) include the OsteoPlug™ for the repair of neurosurgical 
burr holes as well as the OsteoMesh™ and OsteoStrip™ for orbital floor reconstruction. 
 
The second-generation scaffolds produced by FDM are based on composites. Bioactive composite 3D 
scaffolds comprising of a biodegradable polymeric phase (e.g. PCL) and a bioactive phase (e.g. TCP) that 
can bond spontaneously to and integrate with bone are recent innovations in the field of regenerative 
medicine. It was hypothesized that PCL-TCP scaffolds possess cell and protein binding sites due to the 
nucleation of TCP on its surface33,34. The PCL-TCP scaffold was shown to have improved mechanical and 
biochemical properties compared to the first generation PCL scaffolds35-37. The incorporation of TCP into 
a PCL polymer matrix allows tailoring the desired degradation kinetics of the scaffold. PCL scaffolds 
degrade at a slow rate due to its high molecular weight and hydrophobicity. The added TCP particles, 
being hydrophilic, are dislodged from the PCL matrix during degradation and interact with the 
surrounding body fluid shortly after implantation. The dislodgement of TCP creates voids within the 
polymer, thus exposing their surfaces to hydrolytic attack and weakening the overall structure of the PCL. 
By this mechanism, the addition of TCP accelerates the degradation of the PCL polymer. 
 
The scaffold to be used in this study was co-designed by the bioengineering team from the School of 
Chemical and Biomedical Engineering, NTU, led by Prof Teoh Swee Hin and the Oral and Maxillofacial 
Surgery team from the NDCS, led by Dr Goh Bee Tin. The scaffold is conical in shape and available in 2 
different sizes. The small size (5 mm diameter) is suitable for use in incisor, canine and premolar tooth 
sockets while the large size (8 mm diameter) is suitable for use in molar tooth sockets. The unique physical 
properties of the PCL-TCP scaffold allow it to be easily shaped intra-operatively by cutting and shaving 
with a scalpel to fit each individual socket snugly. Customization is therefore not necessary, saving 
production time and cost. The PCL-20% TCP scaffolds will be manufactured by OI using the latest FDM 
techniques (FDM 3000; Stratasys, Eden Prairie, MN), in a class 10K clean room environment. Each 
scaffold will have a lay-down pattern of 0°/60°/120° and porosity of 70%. The PCL-TCP scaffold will 
have a typical honeycomb structure with interconnected equilateral triangles of regular porous 
morphology. It will be individually packed and sterilized using gamma irradiation. 
 
The xenograft, allograft and synthetic materials currently available in the market for this application are 
mostly granular or particulate in form that lacks a 3D structural shape. We postulate that the 3D shape of 
the PCL-TCP scaffold device that can be fashioned intraoperatively to fit snugly within the tooth socket 
will be more effective as a space maintainer during bone healing that favours maintenance of ridge 
dimensions and contour (Figure 2). Results of a pilot clinical trial conducted by our group showed that the 
use of a PCL scaffold for ridge preservation resulted in statistically significant less vertical ridge resorption 
compared to a control group where no scaffold was used38. Moreover, both the fully interconnected 
porosity that enhances cell attachment, as well as the bioactivity of the TCP component promote 
osteogenesis. Previous studies by our group showed direct contact between newly formed bone and the 
PCL or PCL-TCP struts, with no connective tissue interface 38,39. Another major advantage of the PCL-
TCP scaffold over the currently commonly used xenografts and allografts is that, being synthetic, it is 
available in unlimited quantity and its manufacturing technique using FDM is relatively inexpensive. When 
mass produced in the future, the PCL-TCP scaffold can be marketed at a much lower cost (estimated 
between SGD$80 – 100) than materials derived from animal or cadaveric sources. Needless to say, the 
PCL-TCP scaffold also does not pose any danger of disease transmission and is more likely to be accepted 
by different cultures and religions. 
 

Version <No.2>, Dated <15/03/2018> 
Page 10 of 26 
1.2 Rationale and Justification for the Study 
 
Include a description and justification for the route of administration, dosage, dosage regimen, intervention periods, and 
selection of study population. Include a statement of hypothesis. 
 
The research hypothesis is that the insertion of a 3D bioresorbable PCL-TCP scaffold in fresh extraction 
sockets allows for normal bone healing and less resorption of the alveolar ridge after 6 months compared 
to the resorption in extraction sockets without any space filler. 
 
 
1.2.1 Rationale for the Study Purpose 
 
Briefly sketch the background to the current proposal, critically evaluate existing knowledge and specifically identify the gaps 
that the project is intended to fill. 
 
The in vitro characterization of 3D printed PCL-TCP scaffolds has been well studied by our group. The 
design and laydown pattern of the scaffolds were optimized to 0/60/120° in terms of stiffness and 
strength41. Additionally, these scaffolds had a porosity of approximately 60%, with fully interconnected 
pores that facilitated cellular retention as well as media perfusion. Cell culture studies showed fibroblasts 
and osteoblast-like cells could proliferate, differentiate and produce cellular tissue within the scaffolds.  
Mechanically, PCL-TCP scaffolds were shown by our group to have improved stiffness42 over their PCL 
counterparts (Figure 3A, B) while the inclusion of TCP had also conferred bioactivity34,43. On this note, we 
have validated the incorporation of TCP using micro-computed tomography (Figure 3C, D). The 
mechanical response to degradation has also been well characterized, both in vitro and in vivo34,37,42,44 
 
 
 
 
A. In vivo studies of PCL-TCP scaffolds in small and large animal models 
   
Following the in vitro studies, we evaluated the biomechanical properties as well as the degradation and 
safety profiles of the PCL-TCP scaffolds in small animal models of rats37 and rabbits42,45. Importantly, 
these studies demonstrated that PCL-TCP scaffolds were well accepted by the hosts, without causing 
overt inflammatory reaction and fibrous encapsulation. Its safety was also demonstrated by evaluating host 
immunological response in mice40. 
 
Large animal studies were conducted in clinically relevant non-human primate model (Macaca fascicularis) 
for regeneration of tooth socket facial wall defects46 as well as pig model (Sus scrofa) for lateral ridge 
augmentation46 and mandible reconstruction47. In the primate study, we demonstrated that PCL-TCP 
implants resulted in better maintenance of the alveolar contour as compared to autogenous bone grafts at 
6 months (Figure 4a, b)46. In one of the pig studies, we evaluated the use of a PCL-TCP scaffold for lateral 
augmentation of the alveolar ridge over a 6-month healing period (Figure 4c-f). Histological examination 
revealed that new bone matrix and bone marrow were in direct contact with the PCL-TCP scaffold rods 
and invading the interstices, suggesting good biocompatibility and high osteoconductivity39.  
Figure 3 (A) Compressive modulus and (B) 
strength of PCL-TCP scaffolds, mapped 
over a degradation period of 24 weeks37. 
MicroCT visualization of PCL-TCP scaffolds 
on their  (C) top view, and (D) cross-
section view. PCL struts are in grey, while 
TCP particles are distinctly marked in black 

Version <No.2>, Dated <15/03/2018> 
Page 11 of 26 
 
 
 
 
 
B. Pilot randomized controlled clinical trial 
 
A pilot randomized controlled clinical trial was conducted at the NDCS to evaluate the feasibility and 
effectiveness of using a polycaprolactone (PCL) scaffold in fresh extraction sockets for ridge preservation. 
The hypothesis was that the insertion of a 3D bioresorbable PCL scaffold in fresh extraction sockets 
allowed for normal bone healing and better maintenance of ridge dimensions after 6 months as compared 
to extraction sockets without the scaffold. 13 patients were recruited at the NDCS and randomized to 
either the test group (N =6) where a PCL scaffold was inserted in the tooth socket after extraction, or the 
control group (N = 7) where no space filler was used. The results showed less vertical ridge resorption 
in the test group compared to the control group and the difference was statistically significant in the 
mesio-buccal aspect (p=0.008). Micro CT and histological observations showed mainly mineralised bone 
formation in both groups. It was thus concluded that, within the limits of the small sample size, the 
insertion of a 3D bioresorbable PCL scaffold in fresh extraction sockets allowed for normal bone healing 
and there was better maintenance of ridge height after 6 months as compared to extraction sockets 
without the scaffold.38 (Figure 5) 
 
                             
The study which we are proposing in this grant application will be an extension of the above pilot clinical 
trial, except that a second generation composite polymer scaffold PCL-TCP will be used instead of the 
first generation PCL. We expect the results using PCL-TCP will be superior to PCL due to the improved 
biochemical and mechanical properties and degradation kinetics.  
 
 
1.2.2 Rationale for Study Population 
 
Justify selection of target population. 
 
The target population are adult patients who require single tooth extraction and who are suitable for 
dental implant therapy after extraction. This target population has been chosen as the 3D printed 
investigational scaffold device is intended for use immediately following tooth extraction for alveolar ridge 
preservation. The preservation of the alveolar ridge dimensions will be important to create favorable 
conditions for subsequent dental implant placement.  
Figure 5: Insertion of first generation PCL scaffold in tooth extraction sockets resulted in mineralised bone formation and a lack of 
inflammation at 6 months38.  
Figure 4 (a) Particulate autogenous bone and (b) PCL-
TCP scaffold placed during immediate dental implant 
surgery. PCL-TCP scaffold group demonstrated better 
maintenance of the alveolar contour after 6 months46. 
Histological sections of PCL-TCP showing (c) new bone 
matrix (B), which was directly deposited onto a rod of the 
scaffold. (d) Osteoid and osteoblasts (OB) were found in 
close proximity to a rod of the scaffold surrounded by bone 
matrix, B. The formation of (e) bone matrix and bone 
marrow (BM) were also observed at the periphery of a rod 
of the scaffold. Importantly, we note the (f) rare occurrence 
of a few multinucleated giant cells on the surface of the 
PCL-TCP scaffold39.  
 

Version <No.2>, Dated <15/03/2018> 
Page 12 of 26 
 
 
1.2.3 Rationale for Study Design 
 
 
This will be a prospective, open-label, randomized controlled clinical trial. As this study will compare the 
use of a device in a tooth socket (test group) versus no device (control group), blinding is not possible as 
assessors would be able to see the remnants of the scaffold in the socket during 6 months post-extraction. 
To reduce bias, 2 independent parties will perform the ridge dimension.  
 
The investigator performing the Radiopacity Grading Scale will be blinded to the grouping of the 
radiographs. Blinding for the micro CT and histology analyses is not possible as the presence/ absence of 
PCL-TCP scaffold will be obvious in the specimens. 
 
 
2 
HYPOTHESIS AND OBJECTIVES 
 
This study aims to evaluate the efficacy and safety of using a PCL-TCP scaffold for ridge preservation.  
 
2.1 Hypothesis 
 
  The primary hypothesis is that the insertion of a 3D bioresorbable PCL-TCP scaffold in fresh extraction 
sockets allows for normal bone healing and less resorption of the alveolar ridge after 6 months compared 
to the resorption in extraction sockets without any space filler. 
 
 
2.2 Primary Objectives 
 
Primary aim: To evaluate if there will be less alveolar ridge resorption 6 months following tooth extraction 
by the insertion of a 3D printed bioresorbable PCL-TCP scaffold in the tooth socket (test group) 
compared to no space filler in the tooth socket (control group). 
 
 
2.3 Secondary Objectives 
 
 
Secondary aim 1: To compare by clinical observation and histology the healing and inflammatory response 
in tooth sockets of the test and control groups. 
 
Secondary aim 2: To compare using histology and microcomputed tomography (micro CT) the quality and 
quantity of bone tissue formed in tooth sockets in the test and control groups after 6 months. 
 
Secondary aim 3: To evaluate the stability of dental implants placed into healed sockets in the test and 
control groups using Resonance Frequency Analysis (RFA) at the time of placement (stage I implant 
surgery) and at 3 months post-implant insertion (stage II implant surgery). 
 

Version <No.2>, Dated <15/03/2018> 
Page 13 of 26 
2.4 Potential Risks and Benefits:  
 
2.4.1 Potential Risks 
 
There is a possibility that the jaw bone may not be preserved after tooth extraction. A bone graft may be 
needed to build up sufficient bone height and width for favorable implant placement. The attending 
surgeon will advise on the need for bone grafting and this is dependent on various factors such as the 
location of the jaw bone and pre-existing gum diseases. The cost of the bone graft procedure will be borne 
by the patient. 
 
There is a possibility of Infection. In the event of infection, local debridement will be performed. Oral 
antibiotics and chlorohexidine anti-microbial mouthwash will also be prescribed. Exposed parts of the 
scaffold will be trimmed down. If necessary, loose scaffolds and those encapsulated in soft tissue will be 
removed. 
 
2.4.2 Potential Benefits 
 
 
Patients under the test group will be able to gain access to ridge preservation therapies using the novel 3D 
printed scaffold devices before they become widely available. The test group could potentially benefit 
from better ridge preservation. As part of their participation in this research study, the patients from both 
the test and control group will have part of their dental implant treatment cost covered. 
 
This study will contribute to the medical knowledge about the use of the 3D printed biopolymer scaffold 
in ridge preservation. 
 
 
3 
STUDY POPULATION 
 
3.1       List The Number and Nature of Patients to be Enrolled.  
 
This will be a prospective, open-label, randomized controlled clinical trial in adult patients who require 
single tooth extraction and who are suitable for dental implant therapy after extraction. The patient will be 
randomised by a clinician, using sealed envelopes that has been prepared by an independent party, to 
either the test or control group on a 1:1 ratio:  
 
Test Group: insertion of PCL-TCP scaffold after tooth extraction 
Control Group: no space filler after tooth extraction 
 
138 patients who give written consent to participating in the study will be recruited from the Departments 
of Oral & Maxillofacial Surgery and Restorative Dentistry at the NDCS. About 500 patients per year 
receive dental implant treatment at the NDCS. Assuming that 10% of these patients fulfil the inclusion 
and exclusion criteria and give consent to participating in the study, we will expect to recruit about 50 
patients per year. The recruitment of 138 patients is estimated to take about 2 year and 10 months. 
 
 

Version <No.2>, Dated <15/03/2018> 
Page 14 of 26 
3.2      Criteria for Recruitment and Recruitment Process 
 
 
Recruitment posters will be displayed at public locations in NDCS as well as other SingHealth hospitals, 
specialist centres and polyclinics. The study team will also be putting up the recruitment poster on NDCS 
corporate social media to drive interested participants to contact NDCS or to the microsite which will be 
explained in details in the paragraph below. All clinicians in NDCS will be informed of the study via email 
and their help will be sought to identify suitable patients for recruitment into the study. 
 
Letters will be sent to private practitioners to seek for their referrals of suitable patients and the 
recruitment posters will also be placed at these private clinics. 
 
An online microsite will be made available for potential/ enrolled patients to obtain more information 
about the study. Quintiles will be using Facebook advertisements and Google Adwords to drive interested 
individuals to the microsite. Through the microsite, potential patients can fill up an online questionnaire to 
screen for their eligibility. Eligible patients, who pass the online screening, will be contacted by the study 
coordinators to schedule for their first visit. During the first visit, the study investigators will take 
informed consent from the patients, screen for inclusion and exclusion criteria and enrol them into the 
study.  
 
 
3.3      Inclusion Criteria 
 
 
• 
Patient must be above 21 and below 60 years of age. 
• 
Patient must be of American Society of Anesthesiologists (ASA) I or ASA II classification.  
• 
Patient who requires single tooth extraction. 
• 
Patient whose tooth to be extracted is bounded by adjacent teeth. 
• 
Patient who is suitable for dental implant therapy after extraction. 
• 
Patient with any pre-existing infection or abscess at the site of tooth extraction must be treated 
and resolved first prior to inclusion in the study. 
 
3.4     Exclusion Criteria 
 
 
• 
Patient with known allergy to biopolymer materials. 
• 
Patient who are smokers. 
• 
Patient who has undergone therapeutic radiation for head and neck malignant disease. 
• 
Maxillary lateral incisor and molars; or mandibular central and lateral incisor extraction sites. 
• 
Extraction sites with insufficient vertical bone height for implant placement without additional 
bone grafting (such as sinus lift procedure). 
 
4      STUDY DESIGN 
 
 
138 patients who give written consent to participating in the study will be recruited from the Departments 
of Oral & Maxillofacial Surgery and Restorative Dentistry at the NDCS.  
 
Pre-extraction Preparation 

Version <No.2>, Dated <15/03/2018> 
Page 15 of 26 
Dental models and standardised dental radiographs, including periapical and orthopantomogram, will be 
taken. A customised acrylic dental stent will be fabricated as a reference tool for standardised 
measurement of ridge dimensions. Three markings will be made (mesio-buccal, mid-buccal, disto-buccal) 
on the acrylic stent at the intended extraction site (Figure 6) 
 
   
 
Figure 6 
Surgical Extraction and Socket Management 
Under local anesthesia, a trapezoidal buccal mucoperiosteal flap will be raised and an atraumatic extraction 
of the tooth will be performed. The tooth socket will be thoroughly debrided and any granulation tissue 
will be curetted out. The acrylic measuring stent will then be positioned by fitting it to the adjacent teeth 
and the following measurements will be taken using a periodontal probe (PCPUNC15; Hu-Friedy USA): 
 
Ridge height  
This will be measured indirectly as the vertical distance from each reference marking on the stent to the 
marginal bone of the tooth socket at the mesio-buccal, mid-buccal and disto-buccal aspects (Figure 1) and 
will recorded as RHmeb1, RHmib1 and RHdb1 respectively. 
 
Ridge width 
This will be the horizontal distance from the buccal aspect to the lingual/ palatal aspect of the alveolar 
crest at the mid-buccal region of the extraction socket (RW1).  
 
All measurements will be taken by 2 independent parties. Measurements that differ by less than or equal to 
1mm will be averaged. Those that differ by more than 1mm will be repeated and a consensus will be 
reached by the parties. All measurements will be approximated to the nearest 0.5 mm. 
 
The extraction sockets will be managed differently for the test and control groups: 
 
Test Group 
PCL-TCP scaffold: 
The PCL-TCP scaffolds will be supplied by Osteopore International (Singapore). The scaffolds will be 
fabricated by the latest FDM techniques (FDM 3000; Stratasys, Eden Prairie, MN), in a class 10K clean 
room environment. Each scaffold will have a lay-down pattern of 0°/60°/120°, porosity of 70% and will 
be conical in shape. The scaffolds will a typical honeycomb structure with interconnected equilateral 
triangles of regular porous morphology. They will be individually packed and sterilized using gamma 
irradiation. 
 
A suitable size scaffold will be chosen (small or large) based on the tooth to be extracted. During the 
surgery, the scaffold will be shaped by cutting and shaving with a scalpel so as to fit the extraction socket 
snugly at the crestal half to two-thirds aspect. A collagen membrane will be placed over the scaffold at the 
crestal aspect of the socket. The periosteum of the buccal flap will then be incised to allow a tension-free 
primary closure with 4/0 Vicryl® suture. (Figure 7) 
  
 

Version <No.2>, Dated <15/03/2018> 
Page 16 of 26 
 
Control Group  
No space filler will be inserted in the extraction socket but similar to the test group, a collagen membrane 
will be placed over the crestal aspect of the socket and the periosteum of the buccal flap will be incised to 
allow a tension-free primary closure with 4/0 Vicryl® suture.  
 
A periapical radiograph of the extraction site will be taken using standardised settings immediately 
postoperatively. A 5-day course of Amoxicillin (or Clindamycin if the patient is allergic to Penicillin) will 
be prescribed together with an analgesic and chlorhexidine digluconate 0.2% mouthrinse. The sutures will 
be removed 1 week postoperatively. The surgical site will be examined clinically for any signs of infection 
or wound dehiscence. A temporary denture will be issued where necessary. The denture overlying the 
extraction site will be completely relieved.  
 
Stage I Dental Implant Surgery 
Surgical placement of a dental implant will be performed at 6 months after tooth extraction. Radiographs, 
including a periapical of the study site, will be taken before the surgery. Following local anaesthesia and 
elevation of a full-thickness mucoperiosteal flap, the site will be clinically observed for any signs of 
inflammation, infection and presence of fibrous or bone tissue ingrowth. The same customised acrylic 
stent used for the case at the time of the tooth extraction will be used for measuring new ridge height 
dimensions in a manner similar to that described previously. Readings will be recorded as RHmeb2, 
RHmib2 and RHdb2. Ridge width will be measured as previously described and recorded as RW2. 
 
The patient in either the test or control group will be taken out of the study at this stage if it is found that 
the extraction site has undergone extensive bone resorption such as to warrant simultaneous bone grafting 
with implant placement or pre-implant bone grafting with delayed implant placement. 
 
Prior to implant placement, a core of bone of 2 mm diameter and 6 mm length at the healed extraction 
site will be obtained using a trephine bur (3i Implant Innovations Inc.; USA). The core of bone will be 
fixed and stored in 10% neutral buffered formalin and sent for microcomputed tomography (micro CT) 
scanning and histological preparation. 
 
The implant site will be prepared using successive drills, according to the Straumann® (Institut Straumann 
AG, Basel, Switzerland) dental implant surgical protocol. A dental implant (Straumann® Bone Level) of 
the appropriate length and diameter will then be inserted at an insertion torque of between 20 Ncm and 
40 Ncm. After placement of the dental implant, Implant Stability Quotient (ISQ) will be measured by 
Resonance Frequency Analysis (RFA) using the Osstell® machine. A cover screw will be placed over the 
implant. A releasing incision of the periosteum will be done if necessary and the surgical wound will be 
closed primarily with 4/0 Vicryl®.  
 
A 5-day course of Amoxicillin (or Clindamycin if the patient was allergic to Penicillin) will be prescribed 
postoperatively, together with an analgesic and chlorhexidine digluconate 0.2% mouthrinse. The sutures 
Figure 7 

Version <No.2>, Dated <15/03/2018> 
Page 17 of 26 
will be removed 1 week postoperatively. The surgical site will be examined clinically for any signs of 
infection or wound dehiscence. The denture overlying the extraction site will be completely relieved.  
 
Stage II Dental Implant Surgery 
This will be performed 3 months after Stage I dental implant surgery. The site will be observed for any 
signs of inflammation, infection as well as clinical stability of the dental implant. ISQ will be measured by 
RFA using the Osstell® machine before attachment of the healing abutment.  
 
4.1 
Randomisation and Blinding 
 
 
Patients will be randomized after informed consent to the test or control groups at a 1:1 allocation ratio 
using sealed envelopes prepared by an independent statistician. Balanced intervention assignments will be 
achieved using permuted block randomization. Block size will be determined by the statistician 
responsible for generating the randomization list and will not be made known to the clinical investigator 
or site personnel.  
Test Group: insertion of PCL-TCP scaffold after tooth extraction 
Control Group: no space filler after tooth extraction 
 
 
4.2 
Contraception and Pregnancy Testing 
 
 
Not applicable 
 
4.3 
Study Visits and Procedures 
 
 
Summary of Study Visit 
 
 
Please insert visit schedule in this section. 
 
4.3.1 Screening Visits and Procedures 
 
 
Pre-screening: 
Through the online microsite, potential patients will fill up an online questionnaire to screen for their 
eligibility of the following criteria:  
• 
Patient must be above 21 and below 60 years of age 

Version <No.2>, Dated <15/03/2018> 
Page 18 of 26 
• 
Patient who requires single tooth extraction 
• 
Patient whose tooth to be extracted is bounded by adjacent teeth 
• 
Patient who does not have any known allergy to biopolymer materials 
• 
Patient who does not smoke 
• 
Patient who did not undergo any radiotherapy for head and neck cancer 
 
Eligible patients, who pass the online screening, will be contacted by the study coordinators to schedule 
for their first visit.  
 
Visit 1:Consent taking and pre-extraction preparation (Before or on the same day as Visit 2) 
During the first visit, the study investigators will take informed consent from the patients, screen 
for the inclusion and exclusion criteria and enrol them into the study. A model of his/her teeth 
and a radiograph (OPG) will be taken as part of the routine care. 
 
 
4.3.2 Study Visits and Procedures 
 
 
Visit 2: Tooth extraction and insertion of biopolymer scaffold (if applicable, no window period)  
Patient’s tooth will be extracted via surgery. Local anaesthesia will be administered and part of 
subject’s gum will be lifted to expose the tooth to be extracted. After extraction, the socket will be 
thoroughly cleaned and measurements of the socket will be taken. 
If patients have been assigned to the test group (ie. The group that will be receiving the scaffold) a 
piece of the scaffold and membrane will be placed in the socket. The same area of his/her gum 
will be further lifted to aid in the stitching of the gum. 
If patients have been assigned to the control group (ie. The group that will not be receiving the 
scaffold), only a membrane will be placed in the socket. The same area of his/her gum will be 
further lifted to aid in the stitching of the gum. 
After the surgery, a periapical radiograph (estimated radiation exposure less than 0.0083 mSv) of 
the socket will be taken for the research purposes.   
A 5-day course of medication and mouth rinse will be prescribed. 
Visit 3: Removal of stitches (no window period) 
This visit will be scheduled 1 week after Visit 2 or any time before Visit 4. The stitches on patient’s 
gum will be removed and the surgical site will be examined. A temporary denture replacing the 
extracted tooth will be issued, if necessary.  
Visit 4: Pre-implant preparation (± 1 month after Visit 2 or on the same day as Visit 5) 
Periapical radiograph will be taken (estimated radiation exposure of less than 0.0083 mSV) for 
research purposes.  
Another type of radiograph (OPG) and a Cone Beam CT scan will be taken as part of routine care. 
Visit 5: Dental implant surgery stage I (6 months ± 3 weeks after visit 2) 
This visit will be scheduled 6 months ± 3 weeks after Visit 2. During this visit, a dental implant 
will be surgically inserted. Local anaesthesia will be administered. The gum will be exposed and the 
bone ridge will be measured. A small part of the bone (2mm diameter by 6mm) will then be cored 

Version <No.2>, Dated <15/03/2018> 
Page 19 of 26 
from the socket. Removing (coring) a small portion of the bone is routine to an implant surgery. It 
will be collected for research analysis. 
The dental implant will be inserted and the implant’s stability (ISQ) will be measured. If needed, 
the gums at the implant site will be lifted to aid in the stitching of the gum. 
After the surgery, a radiograph (OPG) will be taken as part of routine care. 
A 5-day course of medication and mouth rinse will be prescribed. 
Visit 6: Removal of stitches (no window period) 
This visit will be scheduled 1 week after Visit 5. The stitches on patient’s gum will be removed and 
the surgical site will be examined. The temporary denture will be adjusted to fit if necessary. 
Visit 7: Dental implant surgery stage II (3 months ±3 weeks after visit 5) 
This visit will be scheduled 3 months ±3 weeks after Visit 5. Local anaesthesia will be 
administered and the gums will be cut and lifted to expose the top of the dental implant. A metal 
cap or “healing abutment” will be inserted. The gums will then be stitched around the healing 
abutment. 
Visit 8: Removal of stitches (no window period) 
This visit will be scheduled 1 week after Visit 7. The stitches on patient’s gum will be removed and 
the surgical site will be examined. 
 
 
4.3.3 Final Study Visit: 
 
 
Visit 9: Dental implant review (3 months ± 3 weeks after visit 7) 
The final visit will be scheduled 3 months after Visit 7 where the condition of the gum and 
implant will be reviewed and recorded. 
 
 
4.3.4 Post Study Follow up and Procedures 
 
 
Please refer to section 4. 
 
 
 

Version <No.2>, Dated <15/03/2018> 
Page 20 of 26 
4.4 
Discontinuation/Withdrawal 
 
4.4.1 Discontinuation Criteria 
 
 
Patients presenting with the following will be immediately terminated from the study: 
 Dehiscence defect or excessive loss or fracture of the buccal bony socket wall (> 20% loss) noted 
immediately after tooth extraction 
 Extensive bone resorption of the alveolar ridge noted before Stage I Implant Surgery such as to 
warrant bone grafting procedures before dental implant placement 
 Serious infection or any adverse reaction to the PCL-TCP scaffold noted at anytime during the 
treatment period 
 
 
4.4.2 Discontinuation Visit and Procedures 
 
 
Voluntary withdrawal from study: 
Patients who have not received the test material i.e. PCL-TCP scaffold, shall be offered the appropriate 
standard of care management for tooth loss. 
Patients who have received the PCL-TCP scaffold shall be evaluated 3 months after the date of 
withdrawal for the condition of the gum, particularly any signs of infection or dehiscence and managed 
accordingly. In the absence of any complications, the patient shall be offered the appropriate standard of 
care management for tooth loss. 
 
 
5 
TRIAL MATERIALS 
 
 
 
 
 
5.1 
Trial Product (s) 
 
 
Test Group 
PCL-TCP scaffold: 
The PCL-TCP scaffolds will be supplied by Osteopore International (Singapore). The scaffolds will be 
fabricated by the latest FDM techniques (FDM 3000; Stratasys, Eden Prairie, MN), in a class 10K clean 
room environment. Each scaffold will have a lay-down pattern of 0°/60°/120°, porosity of 70% and will 
be conical in shape. The scaffolds will a typical honeycomb structure with interconnected equilateral 
triangles of regular porous morphology. They will be individually packed and sterilized using gamma 
irradiation. 
 
A suitable size scaffold will be chosen (small or large) based on the tooth to be extracted. During the 
surgery, the scaffold will be shaped by cutting and shaving with a scalpel so as to fit the extraction socket 
snugly at the crestal half to two-thirds aspect. A collagen membrane will be placed over the scaffold at the 
crestal aspect of the socket. The periosteum of the buccal flap will then be incised to allow a tension-free 
primary closure with 4/0 Vicryl® suture. 

Version <No.2>, Dated <15/03/2018> 
Page 21 of 26 
 
Control Group  
No space filler will be inserted in the extraction socket but similar to the test group, a collagen membrane 
will be placed over the crestal aspect of the socket and the periosteum of the buccal flap will be incised to 
allow a tension-free primary closure with 4/0 Vicryl® suture.  
 
 
 
5.2 
Storage and Drug Accountability 
 
 
The PCL-TCP scaffold will be stored between -10 and 25 degrees Celsius (both temperature inclusive).  
 
6 
TREATMENT 
6.1 
Rationale for Selection of Dose 
 
Not applicable 
 
6.2 
Study Drug Formulations 
 
 
Not applicable 
 
6.3 
Study Drug Administration 
 
Not applicable 
 
6.4 
Specific Restrictions / Requirements  
 
 
Not applicable 
 
6.5 
Blinding 
 
 
As this study will compare the use of a device in a tooth socket (test group) versus no device (control 
group), blinding is not possible. To reduce bias, 2 independent investigators will perform the ridge 
dimension. The investigator performing the Radiopacity Grading Scale will be blinded to the grouping of 
the radiographs.  
 
Blinding for the micro CT and histology analyses is not possible as the presence/ absence of PCL-TCP 
scaffold will be obvious in the specimens. 
 
 
6.6 
Concomitant therapy 
 
 

Version <No.2>, Dated <15/03/2018> 
Page 22 of 26 
 
On visit 2 and 5, a 5-day course of Amoxicillin (or Clindamycin if the patient was allergic to Penicillin) will 
be prescribed postoperatively, together with an analgesic and chlorhexidine digluconate 0.2% mouthrinse. 
 
 
 
7 
SAFETY MEASUREMENTS 
7.1 
Definitions 
 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. 
 
A serious adverse event (SAE) or reaction is any untoward medical occurrence that: 
 results in or contributes to death 
 is life-threatening 
 requires inpatient hospitalisation or prolongation of existing hospitalisation 
 results in or contributes to persistent or significant disability/incapacity or 
 results in or contributes to a congenital anomaly/birth defect 
 results in such other events as may be prescribed  
 
7.2 
Collecting, Recording and Reporting of Adverse Events and Serious Adverse Events 
to CIRB  
 
Reporting of adverse events involves the PI submitting to the approving CIRB the completed 
SAE Reporting Form within the stipulated timeframe. PI is responsible for informing the 
institution representative (local SAE resulting in death), sponsor or regulatory bodies as required 
and appropriate. 
 
Reporting timeline to CIRB:  
 
 SAE that result in death, regardless of causality, should be reported immediately - within 
24 hours of the PI becoming aware of the event.  
 Local life-threatening (unexpected/ expected) SAE should be reported no later than 7 
calendar days after the Investigator is aware of the event, followed by a complete report 
within 8 additional calendar days. 
 Local unexpected SAE that are related events, but not life-threatening, should be reported 
no later than 15 calendar days after the investigator is aware of the event. 
 An increase in the rate of occurrence of local expected SAE, which is judged to be 
clinically important, should be reported within 15 calendar days after the PI is aware of the 
event.  
 Local expected SAE should be reported annually (together with Study Status Report for 
annual review). 
 Local unexpected and unlikely related SAE that are not life-threatening should also be 
reported annually (together with Study Status Report for annual review). 
 Local unexpected AE that are related events should be reported at least annually (together 
with Study Status Report for annual review). 

Version <No.2>, Dated <15/03/2018> 
Page 23 of 26 
 Non-local 
unexpected 
SAE 
that 
are 
fatal 
or 
life 
threatening 
and 
definitely/probably/possibly related should be reported not later than 30 calendar days 
after the PI is aware of the event. 
 
7.3 
Collecting, Recording and Reporting of Serious Adverse Events (SAEs) to the 
Health Science Authority (HSA) 
 
All SAEs that are unexpected and related to the study drug will be reported to HSA. All SAEs will 
be reported to HSA.  Please refer to the HSA website for more information on Safety Reporting 
Requirements for Clinical Trials.  
 
The investigator is responsible for informing HSA no later than 15 calendar days after first 
knowledge that the case qualifies for expedited reporting. Follow-up information will be actively 
sought and submitted as it becomes available. For fatal or life-threatening cases, HSA will be 
notified as soon as possible but no later than 7 calendar days after first knowledge that a case 
qualifies, followed by a complete report within 8 additional calendar days. 
 
 
7.4 
Safety Monitoring Plan 
 
 
At each visit, the attending clinician(s) will review the patients’ condition for any complication and other 
safety concerns, both related and/or unrelated to the trial. Appropriate clinical advice will be provided to 
manage the condition. Conditions requiring discontinuation/ withdrawal will be handled as described in 
Section 4.4. 
 
In the case of any injuries during the course of this study, patients may contact the Principal Investigator 
and/or the study team at the telephone numbers indicated in the patient information sheet. Appropriate 
clinical advice will be given to manage the condition. 
 
Please refer to Section 8.1 for the data quality assurance.  
 
 
 
7.5 
Complaint Handling  
 
 
Complaints will be handled by the study coordinator, co-investigators and/or principal investigators. If 
required, an investigation will be conducted by the NDCS research committee, and corrective and 
preventive action plans will be implemented following the committee’s recommendation.  
 
 
8 
DATA ANALYSIS 
8.1 
Data Quality Assurance 
 
 
 
The source document will be recorded and signed off by the appropriate study team member(s) obtaining 

Version <No.2>, Dated <15/03/2018> 
Page 24 of 26 
the respective measurements. The principal investigator will verify and counter-sign on the source 
document to ensure that all the appropriate data has been collected. The recorded clinical trial data in the 
source document will then be entered into an online database by the study coordinators. The principal 
investigator will verify and endorse on the system that the data has been entered correctly. 
 
The sponsor and/or the appointed study monitor will also audit the source document and online database, 
and if required, recommend corrective and preventive action plans to ensure data integrity.  
 
 
8.2 
Data Entry and Storage 
 
 
Source data will be keyed into the eCRF (Oracle system) directly. The access to the source documents will 
be granted to the study coordinators, study team members, sponsors, monitors and/or relevant regulatory 
authorities. 
 
Secured access to the electronic database, via individual password-protected login accounts, will be 
granted to the study coordinators, study team members, sponsors, monitors and/or relevant regulatory 
authorities as required. 
 
 
 
9 
SAMPLE SIZE AND STATISTICAL METHODS 
 
9.1 
Determination of Sample Size  
 
 
The sample size is calculated based on comparison of mean change in aggregate ridge height (mean of 
mesio-buccal, mid-buccal, and disto-buccal ridge heights) at 6-months post extraction between the test 
(PCL-TCP scaffold) and control (no space filler) groups. A sample size of 138 patients (69 per group) will 
be required to detect a difference of 0.5 SD in mean change in aggregate ridge height between the test and 
control groups to achieve 80% power at 5% (two-sided) level of significance, and considering 7% drop-
out rate.    
 
9.2 
Statistical and Analytical Plans 
 
The study will have no interim analysis. A detailed statistical analysis plan for the final analysis will be 
prepared before the database lock.  Briefly, the primary outcome – aggregate change in ridge heights at 6-
months post-extraction will be compared between the test and control groups using the two-independent 
samples t-test. Secondary outcomes - change in individual ridge heights, ridge width, Radiopacity Grading 
Scale, BV%, and ISQ will be also analysed similar to the primary outcome.  
 
 
10 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
The investigator(s)/institution(s) will permit study-related monitoring, audits and/or IRB review and 
regulatory inspection(s), providing direct access to source data/document. 
 

Version <No.2>, Dated <15/03/2018> 
Page 25 of 26 
 
 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
Data will be evaluated for adherence with the protocol and for accuracy in relation to source documents 
by SCRI. Please refer to monitoring plan for scope of monitoring. 
 
12 
ETHICAL CONSIDERATIONS 
 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with the Good Clinical Practice and the applicable 
regulatory requirements. 
 
This final study protocol, including the final version of the Patient Information and Informed Consent 
Form, must be approved in writing by the Centralised Institutional Review Board (CIRB) and regulatory 
approval from Health Sciences Authority (HSA), prior to enrolment of any patient into the study. 
 
The principle investigator is responsible for informing the CIRB and HSA of any amendments to the 
protocol or other study-related documents, as per local requirement. 
 
12.1 Informed Consent 
 
 
Patient will be given time to consider whether or not he/she wants to participate in the project. the patient 
may then bring the PIS home and the consent will be taken at the next visit. However, if the patient is able 
to decide to participate at the first visit, consent will be taken at the first visit. Consent will be taken in 
NDCS outpatient clinic. The place is chosen as it is an enclosed area where the PI is able to explain the 
study and answer patient's queries clearly. 
 
 
 
12.2 Confidentiality of Data and Patient Records 
 
 
 
Research data will be stored in a password protected computer located in the research office. Hard copies 
of the research documents / data collection forms will be stored in locked cabinets in the research office. 
 
Only the study team members will have access to the research data, stored as a registry of patients with 
case number and a study database using only patient case numbers with no other patient identifiers. 
 
13 
PUBLICATIONS 
 
 
Please refer to the publication policy adapted from the International Committee of Medical Journal 
Editors.  
http://www.icmje.org/recommendations/browse/roles-and-responsibilities/  

Version <No.2>, Dated <15/03/2018> 
Page 26 of 26 
 
14 
RETENTION OF TRIAL DOCUMENTS 
 
 
Essential documents will be retained until at least 2-years after the last approval of a marketing application 
in an International Conference on Harmonisation (ICH) region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2-years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be retained 
for a longer period however if required by the applicable regulatory requirements or by an agreement with 
the sponsor.  
 
The sponsor will inform the investigator(s)/institution(s) in writing of the need for record retention and 
will notify the investigator(s)/institution(s) in writing when the trial related records are no longer needed. 
 
15      FUNDING and INSURANCE 
 
 
 
This clinical trial study is supported by NMRC Clinical Trial Grant Co-Development Scheme (CTG-
CO-D) and contributions from both NDCS and Osteopore International (Singapore). Clinical trial 
insurance coverage is obtained by Osteopore International (Singapore). For details, please refer to the 
signed research collaboration agreement (dated 24 December 2014) and addendum (dated 22 December 
2017).