A Randomized, Multicentre, Double Blind, Parallel Study to Evaluate the Performance and Safety of the Zolidd One ExHex Dental Implant Compared to Uncoated One ExHex Dental Implant in Subjects With Partial Edentulism
Phase: NA
Conditions: Partial Edentulism
Sponsor: Addbio AB

Clinical Investigation Plan 
 
Sponsor: AddBIO 
Version: Final Version 3 
 
CIP code: ADD-001 
Date: 2017-07-14 
 
 
 
 
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CLINICAL INVESTIGATION PLAN 
 
NCT Number 
NCT03283241 
Study Title: 
A randomized, multicentre, double blind, 
parallel study to evaluate the performance 
and safety of the Zolidd One ExHex dental 
implant compared to uncoated One ExHex 
dental implant in subjects with partial 
edentulism 
Study Code: 
ADD-001 
Version No: 
Version 3.0  
Date (YYYY-MM-DD): 
2017-07-14 
 
 
 
 

Clinical Investigation Plan 
 
Sponsor: AddBIO 
Version: Final Version 3 
 
CIP code: ADD-001 
Date: 2017-07-14 
 
 
 
 
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CLINICAL INVESTIGATION PLAN 
 
 
 
A randomized, multicentre, double blind, parallel study to evaluate the performance and 
safety of the Zolidd One ExHex dental implant compared to uncoated One ExHex dental 
implant in subjects with partial edentulism 
 
 
 
 
 
Clinical Investigation Plan Code 
ADD-001 
Clinical Investigation Medical 
Devices 
Zolidd One ExHex and uncoated One ExHex dental 
implant  
Indication 
Partial edentulism 
Device Class Zolidd One ExHex 
Medical device class III combination product 
CIP Version 
Final Version 3  
Date 
2017-07-14 
Coordinating/Principle Clinical 
Investigator 
Christer Dahlin, Professor, DDS, 
Käk-kirurgiska Kliniken, Näl 
Lärketorpsvägen 
 
 
461 85 Trollhättan Sweden 
Sponsor 
AddBIO AB 
Teknikringen 10 
583 30 Linköping 
Sweden 
 
 
Revision History: 
 
Protocol final version 1 date 2017-02-08 
First Protocol 
Amendment 1 date 2017-03-10 
Amendment after questions from Ethics committee 
Protocol final version 2 date 2017-06-14 
Minor changes/clarifications including Amendment 
1 2017-03-10 
Protocol final version 3 date 2017-07-14 
Updated after questions from MPA 
 
This clinical investigation will be performed in compliance with ISO 14155:2011, Medical Device Directive 
(MDD) and the Declaration of Helsinki and applicable regulatory requirements. 
 
 
This Clinical Investigation Plan contains privileged or confidential information, which is the property of AddBIO 
AB. Information, may not be disclosed to a third party without written authorisation from AddBIO AB 

Clinical Investigation Plan 
 
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Version: Final Version 3 
 
CIP code: ADD-001 
Date: 2017-07-14 
 
 
 
 
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1 Clinical investigation synopsis 
 
CIP Number  
ADD-001 
Version and 
date 
Final Version 3,  2017-07-14 
Title 
A randomized, multicentre, double blind, parallel study to evaluate the 
performance and safety of the Zolidd One ExHex dental implant compared to 
uncoated One ExHex dental implant in subjects with partial edentulism. 
Sponsor and 
manufacturer 
AddBIO AB 
Investigational 
Device 
Zolidd coated One ExHex and uncoated One ExHex dental implant. 
Objectives  
Primary Objective 
The primary objective is to compare the change in stability from day 1 
(implantation) to 12 weeks after surgery of the “index implant” between 
coated and uncoated implants. 
 
Secondary Objectives  
The secondary objectives Part I: 
• 
To compare absolute ISQ highest values between coated and 
uncoated implants for “index implant” at week 8 and week 12 after 
implantation 
• 
To compare safety as assessed by complications post-surgery and any 
other adverse event up to week 12 between all coated and uncoated 
implants  
• 
To compare change in stability from day 1 to week 8 for the “index 
implant” for coated and uncoated implants 
• 
To compare change in stability day 1 to week 8 and 12 between 
coated and uncoated implants of all other implants 
• 
To compare absolute ISQ highest value at week 8 and 12 between 
coated and uncoated implants of “index implant” and all other 
implants 
• 
To compare change in marginal bone height between coated and 
uncoated implants from day 1 to week 8 and 12 
The secondary objectives Part II: 
• 
To compare safety as assessed by complications post-surgery and 
other adverse events up to month 24 post-implantation visit between 
all coated and uncoated implants  
• 
To compare survival rate of implants up to 24 months between coated 
and uncoated implants for the groups and all  implants 
• 
To compare change in marginal bone height from day 1 to month 12 
and 24 between coated and uncoated implants for the groups  and all  
implants . 
• 
To compare peri-implantitis frequency at 12 and 24 months between 
coated and uncoated implants for the groups and all  implants,  

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Overall 
Investigational 
design 
A randomised, multicentre, double blind, parallel group comparative 
investigation where subjects will be randomised to receive coated or uncoated 
implants.    
The study will consist of two parts (see figure below). Part I, is the main study 
ending when all subjects have reached visit 5. The study will be evaluated and 
Clinical Study Report (CSR) will be written for this part.  
Part II, of the study is a post-follow up study starting when the first subject has 
completed visit 5. There will be a separate CSR written for Study Part II.  
 
The study Part I will begin with a baseline visit, visit 1, Informed consent 
procedure will take place. Provided the subject will give informed consent for 
both Study Part I and Study Part II the screening procedure starts. Subjects will 
undergo all screening and baseline assessment procedures including 
assessments of dental status to determine number of implants needed. 
Subjects who meet all the inclusion criteria and none of the exclusion criteria 
will be given a date for implant surgery within three weeks. The required 
number of implants will be ordered from the Study Distributor. 
 
At the implantation day, visit 2, eligibility will be re-checked before the surgery 
procedures starts. The subjects who still are eligible will enter the treatment 
and the implantation surgery is conducted. The first follow-up visit after 
implantation will take place week 2 post-surgery and the last follow-up visit in 
Study Part 1 will be at week 12. Any post-surgical complications and adverse 
events will be collected and recorded in the eCRF. On demand, depending on 
the outcome of the surgery, additional visits might occur. 
 
Study Part II, the Post Follow-up Study, consist of two visits, one at month 12 
and another visit at month 24 post-surgery. Post-surgical complications and 
adverse events from Study Part 1 will be followed-up if not resolved 
previously. Safety, survival rate and marginal bone loss will be assessed and 
outcome recorded in the eCRF. Additional visits might occur depending on the 
status of the subjects.  
 
Part I 
 
 
 
 
 
 
 
 
                        
Visit 1                    Visit 2 (surgery)     Visit 3                 Visit 4                  Visit 5 
 
Part II (post follow-up) 
 
 
 
 
              Visit 6                          Visit 7 
Baseline 
Zolidd One 
ExHex 
uncoated 
One ExHex 
8 weeks 
12 weeks 
12 months 
24 months 
2 weeks  

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Number of 
subjects 
Seventy subjects will be enrolled to have 62 subjects implanted 
Eligibility criteria 
     
 
 
 
Inclusion Criteria: 
• 
Male or female subjects aged >18 years 
• 
Subjects should be willing to take part, able to understand the 
information given to them, and give written consent 
• 
Subject diagnosed with partial edentulism and who needs at least 
one dental implant in the posterior upper jaw i.e. premolars to first 
molar. The same subject may also need implants in the posterior 
mandible (premolars to first molar region) 
     
Exclusion criteria: 
• 
Suspected to be immunocompromised or are taking 
immunosuppressant 
• 
Current participation in another clinical investigation or participation 
within the last 6 months 
• 
Known sensitivity/allergies to any of the test materials or any of their 
ingredients, such as bisphosphonate, titanium or human fibrinogen 
• 
Significant current or past medical history of hepatic, renal, cardiac, 
pulmonary, digestive, haematological, neurological, or psychiatric 
disease, hypercalcaemia, previous or ongoing malignancy in the head 
and neck region or uncontrolled diabetes type I which in the opinion 
of the Investigator, would compromise the safety of the subject or 
affect the outcome of the investigation   
• 
Pregnant and lactating females or those actively seeking to become 
pregnant in the next 3 months  
• 
Previous (last 5 years) or on-going Bisphosphonate or Denosumab 
treatment 
• 
Significant marginal bone loss prior to implant insertion requiring bone 
grafting or bone graft substitute 
• 
Subject with extraction(s) performed in the position of implant 
placement within the last 2 months 
• 
Subject with need of >6 implants or a full bridge 
• 
The final prosthetic construction in need of support from neighbouring 
teeth 
• 
Known drug or alcohol abuse  
• 
Subject only need implant(s) in the posterior mandible region 
Performance 
and Safety 
Endpoints 
 
The primary efficacy endpoint: 
The primary endpoint is change in stability from day 1 to 12 weeks after 
implantation of the “index implant” comparing coated and uncoated implants. 
This will be assessed in terms of induced micro motion of the implant using 
the Osstell device. The ISQ values are recorded from two directions. The 
directions should be bucco-lingual and mesio-distal, whereof highest value of 
the two measurements will be used.  
The secondary efficacy endpoints Part I: 
• 
Absolute ISQ highest value at week 8 and week 12 after implantation 
for “index implant” 
• 
Incidence of post-surgery complications and adverse events up to 
week 12 post-implantation visit 

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• 
Change in ISQ highest value from day 1 to 8 weeks for the “index 
implant” 
• 
Change in marginal bone height from day 1 to week 8 and 12 for the 
“index implant” 
• 
Absolute ISQ highest value at week 8 and 12 for all implants 
• 
Change in marginal bone height from day 1 to week 8 and 12 for all 
implants 
The secondary efficacy endpoints Part II: 
• 
Post-surgical complications and other adverse events up to month 24 
post-implantation visit for all implants 
• 
Survival rate up to 24 months for all  implants  
• 
Change in marginal bone height from day 1 to month 12 and month 24 
for  all implants 
• 
Occurrence of signs associated with peri-implantitis at month 12 and 
month 24 for all implants 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Investigation Plan 
 
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CIP code: ADD-001 
Date: 2017-07-14 
 
 
 
 
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2 Table of contents   
 
CLINICAL INVESTIGATION PLAN .............................................................................................................. 0 
1 
Clinical investigation synopsis ......................................................................................................... 2 
2 
Table of contents ............................................................................................................................ 6 
3 
Investigator statement and signature............................................................................................. 9 
3.1 Sponsor representative statement and signatures ................................................................. 10 
4 
Clinical Investigators and Clinical investigation administrative structure .................................... 11 
5 
List of abbreviations ...................................................................................................................... 12 
6 
Introduction and study rationale .................................................................................................. 13 
7 
Identification and description of investigational device ............................................................... 14 
7.1 Description of the investigational device ................................................................................ 14 
7.2 Manufacturer details ............................................................................................................... 14 
7.3 Packaging and identification .................................................................................................... 15 
7.4 Randomization and Ordering of Investigational Products ....................................................... 15 
7.5 Study Device and Code Envelopes ........................................................................................... 16 
7.6 Subject populations and indications for use ............................................................................ 16 
7.7 Summary of Training and Experience Necessary for Safe Use ................................................ 16 
7.8 Description of the use of the device ........................................................................................ 17 
8 
Discussion and Justification of Clinical Investigation Design, Including the Choice of Control 
Groups ................................................................................................................................................... 17 
8.1 Clinical Investigation design and choice of control group ....................................................... 17 
8.2 Prior and Concomitant Medication and other Dental Procedures .......................................... 17 
9 
Risk and benefit analysis ............................................................................................................... 17 
9.1 Anticipated clinical benefits ..................................................................................................... 17 
9.2 Anticipated adverse device effects .......................................................................................... 18 
9.3 Residual risks identified in risk analysis report ........................................................................ 18 
9.4 Risks associated with participation in the clinical investigation .............................................. 19 
9.5 Possible interactions with concomitant medical treatments .................................................. 19 
9.6 Steps to be taken to control or mitigate risks.......................................................................... 19 
9.7 Risk-Benefit conclusion ............................................................................................................ 19 
10 
Objectives and hypotheses for the clinical investigation ........................................................ 20 

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10.1 
Primary objective ................................................................................................................. 20 
10.2 
Secondary Objectives .......................................................................................................... 20 
10.3 
Hypotheses .......................................................................................................................... 20 
11 
Design of the clinical investigation .......................................................................................... 21 
11.1 
Primary and secondary endpoints ....................................................................................... 21 
12 
Investigational device treatment ............................................................................................. 21 
12.1 
Description of the device technique to be used.................................................................. 21 
12.2 
Description of investigational devices ................................................................................. 21 
12.3 
Description of equipment used for assessment during investigation ................................. 22 
13 
Study schedule, visits, procedures and assessments .............................................................. 22 
13.1 
Study visits and Schedule of events .................................................................................... 23 
14 
Study population ...................................................................................................................... 26 
14.1 
Enrolment of subjects .......................................................................................................... 26 
14.2 
Informed consent procedures ............................................................................................. 26 
14.3 
Subject screening and Subject identification logs ............................................................... 27 
14.4 
Prohibited concomitant therapy ......................................................................................... 28 
14.5 
Premature termination ........................................................................................................ 28 
14.6 
Termination or suspension of the study ............................................................................. 28 
15 
Adverse Events/Adverse Device Effect, Serious Adverse Event/Serious Adverse Event Effect 
and Device Deficiencies ........................................................................................................................ 28 
15.1 
Definition of Adverse events (AE) ........................................................................................ 28 
15.2 
SAE reporting and Emergency contact details .................................................................... 31 
16 
Monitoring ............................................................................................................................... 32 
16.1 
Subject Records and Source Data ........................................................................................ 33 
16.2 
Access to Source Data and Documentation ........................................................................ 33 
17 
Quality assurance ..................................................................................................................... 33 
18 
Statistical considerations ......................................................................................................... 33 
18.1 
Statistical and analytical plans ............................................................................................. 33 
18.2 
General methodology .......................................................................................................... 34 
18.3 
Statistical hypothesis ........................................................................................................... 34 
18.4 
Analyses Datasets (statistical populations) ......................................................................... 35 
18.5 
Performance Analyses ......................................................................................................... 35 
18.6 
Safety analysis ..................................................................................................................... 36 
18.7 
Analysis of baseline variables .............................................................................................. 36 

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18.8 
Determination of sample size .............................................................................................. 36 
18.9 
Randomisation procedure ................................................................................................... 36 
18.10 
Expected drop-out rates ...................................................................................................... 37 
18.11 
Interim analysis .................................................................................................................... 37 
18.12 
Reporting deviations from original statistics plan ............................................................... 37 
18.13 
Sub-group analysis plans ..................................................................................................... 37 
18.14 
Handling missing or spurious data ...................................................................................... 37 
18.15 
Subject distribution in multicentre studies ......................................................................... 37 
19 
Data management ................................................................................................................... 37 
19.1 
The web-based e-CRF .......................................................................................................... 37 
19.2 
Data, database validation, query resolution, security and access ...................................... 38 
19.3 
Data retention ..................................................................................................................... 38 
19.4 
Data QA procedures ............................................................................................................ 38 
20 
Amendments to the clinical investigation plan ....................................................................... 38 
21 
Clinical investigation plan deviations ....................................................................................... 39 
22 
Device accountability procedures and storage........................................................................ 39 
23 
Statement of compliance ......................................................................................................... 39 
23.1 
Relevant ethical and regulatory standards and guidelines ................................................. 39 
23.2 
Clinical indemnity insurance provision ................................................................................ 40 
24 
Publication policy ..................................................................................................................... 40 
25 
List of references...................................................................................................................... 41 
26 
APPENDICES ............................................................................................................................. 44 
26.1 
Appendix I Declaration of Helsinki ...................................................................................... 44 
26.2 
Appendix 2 Instructions for Use .......................................................................................... 50 
 .............................................................................................................................................................. 50 
 
 
 

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3 Investigator statement and signature  
I confirm that I have carefully read and understood this CIP and agree to conduct the study 
accordingly. I am aware of, and will comply with the ethical principles that have their origin in the 
current version Declaration of Helsinki, Good Clinical Practice and all applicable regulatory 
requirements in that the rights, safety, privacy and well-being of study subjects are protected. I 
agree to appropriately direct and assist the staff under my control, who will be involved in the study. 
The signature below constitutes the approval of this CIP and appendices, and provides the necessary 
assurances that this study will be conducted according to all stipulations of the CIP. 
 
 
 
Clinical Site: NÄL, Trollhättan 
 
Site No: 01 
 
 
Principal Investigator 
 
Print Name__________________________    Title____________________________ 
 
 
  
                                                                                                                                     
Signature                                                                                Date 
  
  
 
  
  
  
 
 

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3.1 Sponsor representative statement and signatures 
 
The undersigned have read this investigation plan and hereby confirm that, to the best of their 
knowledge, it accurately describes the investigation to be conducted. The signature below 
constitutes the approval of this CIP and appendices.  
 
 
 
CEO 
Ulf Sewerin 
 
 
 
_______________________ 
_________________ 
AddBIO  
 
 
 
Signature 
 
 
Date 
Linköping 
Sweden 
 
 
CTO 
Anders Petersson 
 
 
_______________________ 
_________________ 
AddBIO  
 
 
 
Signature 
 
 
Date 
Linköping 
Sweden 
 
 
Statistics 
Nils-Gunnar Pehrsson 
 
 
_______________________ 
_________________ 
 
CEO/Senior Biostatistician  
 
Signature 
 
 
Date 
Statistiska Konsultgruppen 
Göteborg 
Sweden 
 
 
 

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4 Clinical Investigators and Clinical investigation administrative 
structure 
Study role 
Name, title, address, and e-mail 
Phone No 
Coordinating 
investigator 
Christer Dahlin, Professor, DDS, 
Käk-kirurgiska Kliniken, Näl 
Lärketorpsvägen  
 
461 85 Trollhättan Sweden 
 
Email: dahlinchrister@hotmail.com 
+46 (0) 70 5332557 
+46 (0) 522 92166 
Other Investigators  
A list of other investigators and personnel at 
site will be filed in the ISF and SMF. 
 
Sponsor representative 
Ulf Sewerin, CEO 
Email: ulf.sewerin@addbio.se 
 
Anders Petersson, CTO 
Email: anders.petersson@addbio.se 
 
AddBIO AB 
Teknikringen 10 
583 30 Linköping 
Sweden  
Email: info@addbio.se 
 
+46 (0)708797988  
 
+46 (0) 709 741269 
 
 
 
+46 (0) 13 21 00 6 
 
 
Other Sponsor 
representative 
Annelie Andersson Clinical Study Manager 
Consultant 
Email: annelie.andersson14@gmail.com 
+46(0) 723 00 53 16 
Medical Monitor  
Irene Herrmann, DDS, PhD 
Consultant 
Södra Småskolevägen 41 
429 44 Särö 
Email: ireneeherrmann@hotmail.com 
+46 (0) 708 93 66 13 
Monitor 
Irene Herrmann, DDS, PhD 
Consultant 
Email: ireneeherrmann@hotmail.com 
+46 (0) 708 93 66 13 
Biostatistician 
Nils-Gunnar Pehrsson 
 
Statistiska Konsultgruppen 
Göteborg 
Sweden 
Email: ngp@stat-grp.se 
+46 (0) 709 63 36 13 
Data Management 
Pharma Consulting Group AB (PCG) 
Kungsängsvägen 19 
75323 Uppsala 
Sweden 
+46(0)18 430 3100 
Blinding and Distribution 
to site 
Inpac i Lund AB 
Åldermansgatan 2 
227 64 Lund 
Sweden 
Email: peter.thulin@inpacpharma.com 
+46 (0) 46 280 2800 
 
 

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5 List of abbreviations  
AE  
 
Adverse Event 
ADE  
 
Adverse Device Effect 
ASADE  
Anticipated Adverse Device Effect 
ASTM  
American Society for Testing and Materials, 
CA 
 
Competent Authority 
 
CE 
 
Conformité Européenne (conforms to European Product Directives)  
CIP 
 
Clinical Investigation Plan 
CRO 
 
Clinical Research Organisation 
CSA 
 
Clinical Study Agreement 
CSR 
 
Clinical Study Report 
CBCT 
 
Cone Beam Computed Tomography 
DD  
 
Device Deficiency 
DMFT  
Decayed Missed Filled Teeth 
eCRF   
electronic Case Report Form 
EC  
 
Ethics Committee 
EMA 
 
European Medical Agency 
IB 
 
Investigator Brochure 
IFU 
 
Instruction for Use 
ISF 
 
Investigator Study File 
ISQ 
 
Implant Stability Quotient 
 
GCP 
 
Good Clinical Practice 
ISO 
 
International Standard Organization 
ITT  
 
Intention-to-Treat 
LOCF 
 
Last Observation Carried Over 
MDD   
Medical Device Directive 
MedDRA 
Medical dictionary Drug Regulatory Affairs 
NAMSA  
Independent laboratory 
ONJ 
 
Osteonecrosis of the jaw 
PP  
 
Per Protocol 
PT 
 
Preferred term 
QA  
 
Quality Assurance 
SADE 
 
Serious Adverse Device Effect 
SAE  
 
Serious Adverse Event 
SAP   
 
Statistical Analysis Plan 
SD 
 
Standard Deviation 
SOC 
 
System Organ Class 
SOP                  
Standard Operating Procedures 
SMF 
 
Study Master File 
SMP 
 
Study Monitoring Plan 
USADE   
Unanticipated Serious Adverse Device Effect 
 
 
 

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6 Introduction and study rationale 
Subjects undergoing dental surgery and treatment for the replacement of damaged, decayed or 
missing posterior maxillary teeth generally face up to 9 - 12 months from initial removal to full usage 
of their new dental implants1-5.  Part of this time is linked to healing of bone and gum after initial 
removal of the subject’s own teeth (3-4 months typically), followed by another 3-6 months period 
whilst the implant is allowed to integrate with the host bone before the final ceramic tooth can be 
placed onto its supporting implant6. 
 
Work is on-going to try and shorten this period of time to improve subject’s satisfaction with this 
treatment option. The use of bone graft substitutes at the time of initial surgery to get better bone 
healing and restoration of gum height has been investigated 7-10.  
 
The ability to improve and shorten the time to the initial integration of the implant within the 
jawbone are an obvious target for improvement.  It is this element of the treatment that AddBIO 
seeks to address with the Zolidd One ExHex implant.   
 
The Zolidd One ExHex implant consists of generic model of the well-established Nobel Biocare 
Brånemark MkIV implant, where the surface has been coated with the Zolidd coating. 
The Zolidd coating is a nano coating combination of heated fibrinogen and zoledronic acid which 
adheres to the surface of the screw thread profiles11-14.  This coating is intended to enhance the 
bone integration properties of the dental implant. It will be necessary for the Notified Body to gain 
extra clearance for the pharmaceutical and blood derivative portions of the combination, from the 
EMA, before granting final CE Mark approval.   
 
This clinical investigation is designed to obtain the necessary confirmatory data of the safety and 
performance of the use of Zolidd One ExHex implants in subjects with partial edentulism.  Subjects 
will be randomised to receive either Zolidd One ExHex implants or uncoated One ExHex implants. 
Any one subject will receive a maximum of 6 implants. 
 
A detailed risk- benefit assessment and potential risks due to the investigational procedures are 
addressed in chapter 9 of this document and in the IB.  In this introductory chapter a summary of the 
main potential issues are discussed.  
 
Implant stability in terms of induced micro motion will be measured during the study with the ISQ 
device from Osstell. Several papers have been published which use this technique to demonstrate 
the degree of fixation of the implant within the bone prior to attachment of the appropriately sized 
dental cap.  The results show excellent sensitivity between loose and fixed implants15-23.  It could be 
a minor risk for loosening of integration when performing ISQ measurement as early as 8 and when 
loading at 12 weeks as discussed in chap 9. 
 
In addition radiographic outcome will be assessed to further evaluate clinical performance. There 
will be intra-oral radiographs taking at two additional times compared to standard treatment in this 
study. These extra radiographic evaluations are not assumed to add on any potential risks for the 
subjects. See chap 9.4 in this document for details. 
The biocompatibility of the coating has been evaluated by AddBIO in accordance with the 
established standards. Previous implantations of Zolidd prototype coated implants in both animals 
and humans have not showed any signs of biocompatibility related problems31, 14, 32, 33. There is 

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however still a risk that a patient will experience adverse reactions associated with hypersensitivity 
to the coating components34, 35. 
Patients suspected to be immune-compromised or are under immune-suppressant treatment will be 
excluded (see exclusion criteria chap 14.3.3). 
 
The patient and the surgeon will be informed that patients with known hypersensitivity to any of the 
product constituents should not be treated with the Zolidd One ExHex implant. 
 
As discussed above the Zolidd coating consists of a nano-coating combination of heated fibrinogen 
and zoledronic acid which adheres to the surface of the screw thread profiles.  The main safety issue 
of concern is related to the use of zoledronic acid and this has been thoroughly investigated.  There 
have been pre-clinical and clinical investigations on Zolidd prototype coated implants where no 
adverse device effects have been identified13, 14. It should be noted that safety concerns have been 
raised in the literature and those concerns are associated with long term high dosage treatment with 
bisphosphonates, leading to osteonecrosis of the jaw (ONJ) when being used to treat metastatic 
disease etc. in subjects with contributory dental hygiene cofactors.  There has been no incidence, 
observed to date, for osteonecrosis of the jaw occurring in the human studies conducted where 
bisphosphonates have been applied as a coating on the implant or by direct local bone application 
during surgery13, 14. Thus, there was no significant hazards identified to suggest that the use of 
RiaSTAP or Zoledronic Acid at the levels obtained in Zolidd coating that would have detrimental 
effect upon the safety of the subjects. For more detailed information see chap 9 and the IB.  
 
The risk- benefit ratio of Zolidd One ExHex implant in subjects with partial edentulism is judge to be 
favourable. The major benefit of the Zolidd One ExHex implant is expected to be a shortening of the 
time for healing while giving a stable implant in areas were the bone quality is not optimal.  
 
 
7 Identification and description of investigational device 
7.1 Description of the investigational device 
The test implant, Zolidd One ExHex, and the control implant One ExHex consist of a generic model of 
the established Brånemark dental implant. The test implant is coated with Zolidd and the control 
implant is uncoated. Zolidd is a nano-coating combination of heated fibrinogen and zoledronic acid 
which adheres to the surface of the thread profiles of the dental implants.  This Zolidd coating is 
aimed to enhance the bone integration properties, by strengthening the bone surrounding the 
implant. The control implant One ExHex is blasted and cleaned according to the same protocol as the 
coated implant. The only difference between the control and the coated implants are the addition of 
Zolidd. More details of the coating, individual constituents and the One ExHex implant 
manufacturing are included in the IB. Both of the coating ingredients of the Zolidd coating have a 
long established history of use as pharmaceuticals.  
 
7.2 Manufacturer details 
The legal manufacturer of coated Zolidd One ExHex and uncoated One ExHex is AddBIO AB, 
Teknikringen 10, 583 30 Linköping, Sweden. The screw shaped implants and coating of the implants 
are manufactured for AddBIO by Elos Medtech Timmersdala AB using specially designed equipment. 
Final sterilization with gamma irradiation will be conducted by Steris.   

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7.3 Packaging and identification  
The coated implant is placed in a custom-made titanium tube with screw on lids, before packaged in 
a sterile barrier Tyvek pouch. The tube will avoid any potential migration of polymer molecules from 
vapours generated in the pouch sealing process as well as from surface contact with the inner 
pouch. The inner pouch is place in an outer pouch (Natural Poly bag) that will act as a moist barrier. 
Finally, the outer pouch is placed in a carton capsule where a product label is placed. The product 
label is design as in the figure below. Labelling will be in compliance with 93/42/EEC and applicable 
harmonized standards. The text “For Investigational Use Only” will be added. The device will be 
sterilized using gamma irradiation, in accordance with ISO 11737-1, the sterilization method and the 
package is being validated to confirm product sterility at one year shelf-life. The boxes will be sent to 
the distributor, Inpac in Lund AB, who will function as a storage depot for the investigational 
products. The distributor will also be responsible for blinding the products and adding information to 
the labels as detailed in the figure below.   
 
 
 
Figure 1 Product label 
7.4 Randomization and Ordering of Investigational Products 
Once a subject has been enrolled into the study the investigator allocates a study number to the 
subject selected, in sequential order, from the Site Specific Subject Number List.  
The investigator adds this number to the eCRF and contacts the distributor, Inpac in Lund AB, by e-
mail as follows: 
 
- 
order@inpacpharma.com 
 
The investigator informs the distributor, via email, of the subject’s study number and number of 
implants needed for the subject. The distributor acknowledges the order, in return e-mail to the 
investigator, and provide the date of delivery of the implants.   
 
The distributor will allocate treatment to the subject according to the randomization list provided by 
Statistiska Konsultgruppen Göteborg, Sweden. This group will also provide treatment code 
envelopes. The code envelops will be set to each participating site prior to study start. Subjects will 
be randomly assigned to receive either coated or uncoated implants to a ratio 1:1.   
 
AddBIO AB 
Teknikringen 10 
SE-583 30 
Linköping, Sweden 
+46 - (0)13 21 00 60 
XXXXXX 
Tandimplantat Zolidd One ExHex/ Placebo 
<DIAMETER> x <LENGTH> mm 
YYYY-MM 
Antal: XXXXXX 
Titanlegering 
Ansvarig tandläkare: 
________________________ 
Behandlingsnummer: 
________________________ 
Patientnummer: 
________________________ 
Produkten är endast avsedd för klinisk studie ADD-001 
Produkten innehåller humant blodderivat 
To be completed by 
Distributor before sent 
Masked by Distributor 
to keep investigators 
blind 

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In a controlled way, per allocated randomization number, the distributor will select the number of 
implants ordered by the investigator and blind the lot number of the implants.  Subject’s study 
number, allocated treatment number (same as randomization number) and site details (see Fig 1) 
will be added to the labels.   
 
Once the Distributor has processed the order the labelled and packaged implants will be sent to the 
site. Email will be sent to the investigator with shipment details including the tracking number. The 
investigator will inform the Distributor when the shipment has arrived at site. 
7.5 Study Device and Code Envelopes   
The investigator will maintain accurate records of all device supplies, including the dates on which 
device supplies were received from the Distributor (see chap 22).   
The identity number of the implant for each randomized subject will be captured in subject’s eCRFs. 
The same information will be documented in the subject’s clinical record.  
 
 
The treatment code envelopes will be kept at the site in a secure place. The location of where the 
code envelopes are kept must be documented in the subject’s clinical record. In case of emergency 
and at the discretion of the Investigator the code envelope may be opened. If the code is broken this 
must be documented on the code envelope and in the subject’s clinical record. Date and name of 
the investigator who decided to break the code and the reason will be recorded. At the end of the 
study the code envelops will be collected and forwarded to the sponsor.  
 
Unused products, still residing with the investigator at the end of study are to be returned to AddBIO 
for destruction after accountability has been performed. 
 
7.6 Subject populations and indications for use 
The sources for recruitment are subjects using the study clinics for their dental care and subjects 
who are referred to the study clinics from other dental care units. The Zolidd coated One ExHex 
dental implants are intended to primarily treat subjects requiring replacement of posterior maxillary 
teeth and as a secondary objective replacement of teeth in the mandibular region. These subjects 
may suffer from untreatable decay, periodontal disease or an edentulous area. Subject presenting 
with a maximum of 6 teeth requiring replacement are the target population for the investigation 
provided they comply with all eligibility criteria and agree to the study procedures. 
7.7 Summary of Training and Experience Necessary for Safe Use 
All investigators involved in this investigation must be highly experienced in the technique used (Ad 
Modum Brånemark) and in other current conventional treatments available. At the Site Initiation 
Visit the investigators and other site staff participating in the study will be trained by a sponsor 
representative on how to use the device in accordance with the instructions for use (IFU) and the 
ISQ measurement technique. All protocol procedures, with particular attention to subject eligibility 
criteria, adverse event reporting, ISO 14155 GCP requirements, informed consent procedures and 
maintenance of investigator study file (ISF) will be addressed.  
 
The Investigators will maintain records of all site personnel involved in the clinical investigation and 
complete a delegation list to clarify roles and responsibilities at the study site. The Investigators will 
ensure that, with the support of the sponsor, appropriate training relevant to the study is given to 
the site personnel involved in the study and that any new information of relevance for the conduct 
of the study is forwarded to all personnel involved. 

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7.8 Description of the use of the device 
Full details of the operative technique for the study implants are included in the investigators 
brochure and the IFU. It is worth noting that the technique used within the study remains the 
standard technique employed for insertion of similar designed implants as in routine practice. 
 
8 Discussion and Justification of Clinical Investigation Design, 
Including the Choice of Control Groups 
8.1 Clinical Investigation design and choice of control group 
The study design (randomized, double blind, parallel groups) was chosen to evaluate the performance 
and safety of the Zolidd One ExHex dental implant with the uncoated One ExHex implant in subjects 
with partial edentulism in need of 1-6 implants.  
  
During the baseline visit written informed consent for both Study part I and Study Part II will be 
collected together with demographics, dental status, medical history and concomitant medications. 
 
At the implantation visit the eligibility criteria will be re-checked to confirm that nothing has changed 
from baseline to surgery before starting any surgical procedures. 
 
At week 8 and week 12 post-implantation surgery the stability test will be performed using ISQ 
technique and change in marginal bone height will be measured. Any post-surgical complications and 
adverse events will be collected and recorded in the eCRF. On demand, depending on the outcome of 
the surgery, additional visits might occur. 
 
The primary endpoint is stability at 12 weeks after implantation comparing coated and uncoated 
implant. This will be assessed in terms of induced micro motion of the implant using the Osstell 
device. The ISQ values are recorded from two directions. The directions should be bucco-lingual and 
mesio-distal, whereof highest value of the two measurements will be used for the statistical 
analyses.  
8.2 Prior and Concomitant Medication and other Dental Procedures 
Medication, which is considered necessary for the subject safety and well-being, may be given at the 
discretion of the Investigator. At each study visit the Investigator will check for any changes and 
update the eCRF accordingly. 
Investigators will be advised to encourage the subjects to avoid, during the 12 week study period, 
any dental procedures that could influence study endpoints. Dental procedures needed for the 
safety of the subjects are excluded from this advice. If a dental procedure is undertaken the clinical 
investigator must be informed immediately. 
 
9 Risk and benefit analysis 
9.1 Anticipated clinical benefits 
It is anticipated that the Zolidd One ExHex implant will improve implant stability at 8 and 12 weeks 
and provide a safer and stronger integration which is a concern especially in compromised bone. 
Therefore, it is expected that at the time of final prosthetic reconstruction subjects treated with 
Zolidd One ExHex implants will receive a safer and more predictable stability compared to subjects 
with uncoated One ExHex implants. This would then present an obvious benefit due to the 

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improvement in time taken for a subject receiving their final prosthetic reconstruction and a more 
predictable outcome when the bone quality is poor.  
9.2  Anticipated adverse device effects 
The most common early post-surgical symptoms in dental implant surgery are swelling, pain, 
numbness of nerve and/or infection. 
 
 
Further problems in common include problems associated with failure of the integration or fracture 
of the implant and/or subsequent loosening, causing revision surgery. These problems may occur 
but are expected to be of low frequency since the investigational devices used in this study are 
designed as a generic model of the established Nobel Biocare Brånemark implant with low frequency 
of such problems. 
 
Known risk factors for long term success are insufficient bone volume, infection, inadequate soft 
tissue, uncontrolled diabetes, smoking, bruxism, unfavourable jaw relationships, or-facial 
radiotherapy, and steroid therapy, systemic treatment with bisphosphonates or chemotherapy. The 
same general precautions apply in this clinical investigation as with any dental implant surgery. 
9.3  Residual risks identified in risk analysis report 
As part of the risk management process all anticipated risks were reviewed and were either 
eliminated or reduced to an acceptable level. This process was conducted in line with ISO 14971. 
 
To minimize implant design risks AddBIO has chosen to design the Zolidd One ExHex as a generic 
model of the established Nobel Biocare Brånemark MkIV implant, used for decades with high 
success-rates.  
 
In dental implant surgery, the risk of bisphosphonate related osteonecrosis of the jaw (ONJ) is well 
known. This condition is however related to long-term systemic bisphosphonate treatment. It should 
be noted that the Zolidd surface, the amount of bisphosphonate, is very low when compared to a 
systemic injection. It is also known that local treatment with bisphosphonates is less prone to ONJ 
than systemic treatment 12 and not any of the previous studies performed in animal models 
exhibited any signs of ONJ14, 30-32. There has been no incidence observed for osteonecrosis of the jaw 
in the two human studies conducted where bisphosphonates have been applied as a coating on the 
implant or by direct local bone application during surgery13, 14. For more information see the IB. For 
this reason, the risk of causing osteonecrosis of the jaw is deemed as negligible.  
 
The fibrinogen concentrate used in the coating (RiaSTAP®, CSL Behring, Germany) is derived from 
human blood plasma pools as documented by CSL Behring certificate of analysis. CSL Behring has its 
own plasma collection centres and an Integrated Safety System in place to ensure that all of its 
plasma products, including RiaSTAP®, meet the highest possible safety standards. Despite the above 
standard measures, when medicinal products prepared from human blood or plasma are 
administered, the possibility of transmitting infective agents cannot be totally excluded. Given the 
broad use and rigorous quality control of RiaSTAP, it is AddBIOs conclusion that the risk probability is 
extremely low and that the potential benefit of the Zolidd coating thus outweighs this risk. More 
information is available in the IB. The patient will be informed about the potential risk of 
transmission of pathogens through the patient information form. 
 

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9.4  Risks associated with participation in the clinical investigation 
ISQ measurement is performed at 8 and 12 weeks with the aim to measure the stability of the 
implants. There is a minimal risk for loosening of integration when testing the integration already at 
8 weeks and when loading the implants at 12 weeks. However, if loosening of integration would 
happen the implant can be either left in-situ for prolonged healing or replaced with a larger 
diameter implant.  Replacement of a failed implant will be made by commercial brand at the 
discretion of the Investigator. 
 
Standard procedure prior to determining if the subject is a candidate for dental implant treatment 
will be applied. It involves adequate and individual radiographic evaluations in order to establish 
bone quality and quantity as well as location of anatomical structures in the area of implantation. 
 
Furthermore, participation in the study involves intra-oral x-ray films on 5 occasions and 1 pre-
surgery CBCT scan or alternative radiograph for bone quality and quantity evaluation. Of these 6 
radiographic evaluations, two are extra for taking part in this study. Taking worst case scenario 
where subject has the maximum 6 implants widely spread through-out the mouth this would mean a 
maximum of 6 images per radiographic assessment, of which would be a maximum of 5 time points 
(post-implantation 2, 3, 12 & 24 months), and one CBCT pre-surgery. 
 
Each bitewing/intra oral film delivers a dose of 0.5 micro Sieverts, the maximum exposure would be 
1x1000 (CBCT) and 6x5x0.5 = 1015 micro Sieverts in 24 months. This compares to the typical 
background irradiation level in Sweden of  1000 micro Sieverts per year. Thus, it equates to 
1015/2000 = 50% compared to background dose over a period of 2 years.  
 
Additional known or expected risk in this clinical study are those that would be expected for normal 
routine treatment of this condition with currently available treatment alternatives. In addition, there 
is a risk for allergies or other reactions of the surface treatment with the bisphosphonate and blood 
protein. These risks are very small as the dose is 1000 times lower of the bisphosphonate and the 
blood protein used clinically. Subject with known sensitivity/allergies to the test material or any 
ingredients are excluded from participation, see exclusion criteria. 
9.5  Possible interactions with concomitant medical treatments 
Currently there is no indication to suspect any potential interactions between Zolidd coated One 
ExHex implants and routine existing subject concomitant medications. 
9.6  Steps to be taken to control or mitigate risks 
The Zolidd One ExHex dental implant has been reviewed as part of the risk management process in 
accordance with ISO 14971:2012, for all stages of the product’s lifecycle. The risk management will 
be updated throughout the development process until all risks have been mitigated as far as can be 
reasonably expected and where the benefits of the device can be deemed to outweigh the residual 
risks.  
9.7  Risk-Benefit conclusion 
The major benefit of the Zolidd One ExHex implant is expected to be a shortening of the time for 
healing while giving a stable implant in areas were the bone quality is not optimal. Risks have been 
mitigated as far as possible and the risk-benefit ratio of using Zolidd One ExHex for partial 
edentulous subjects participating in this investigation is judged to be favourable (benefit is higher 
than risk).  

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10 Objectives and hypotheses for the clinical investigation 
The objective of this investigation is to evaluate the efficacy and safety of Zolidd One ExHex implants 
when used for the intended purpose. Primary evaluation will be week 12 after implantation at end 
of Study Part I. Data will continue to be collected at month 12 and 24 for a second analysis at 24 
months after implantation as part of the Post Follow-up of the device Part II. 
 
Where a subject receives more than one implant, the most posterior maxillary implant will be 
considered to be the “index implant”, which will be assessed for performance as primary objective.  
In a case where the subject also has mandibular implants more posterior than the most posterior 
maxillary implant the maxillary implant will still be considered to be the “index implant”.   
 In a case where subject have bilateral teeth in same location the investigator will be free to select 
one of these teeth to be the “index implant”, but will document his reasoning for selection before 
implantation and shall be recorded in eCRF. 
All implants will be followed regardin safety and performance (efficacy) however the “index implant” 
will as primary be comparing coated and uncoated devices 
10.1 Primary objective 
The primary objective is to compare the change in stability from day 1 (implantation) to 12 weeks 
after surgery of the “index implant” between coated and uncoated implants. 
10.2 Secondary Objectives  
The secondary objectives Part I: 
- 
To compare absolute ISQ highest values between coated and uncoated implants for “index 
implant” at week 8 and week 12 after implantation 
- 
To compare safety as assessed by complications post-surgery and any other adverse event 
up to week 12 between all coated and uncoated implants  
- 
To compare change in stability from day 1 to week 8 for the “index implant” for coated and 
uncoated implants 
- 
To compare change in stability day 1 to week 8 and 12 between coated and uncoated 
implants of all other implants 
- 
To compare absolute ISQ highest value at  week 8 and 12 between coated and uncoated 
implants of “index implant” and all other implants 
- 
To compare change in marginal bone height between coated and uncoated implants from 
day 1 to week 8 and 12 
 
The secondary objectives Part II: 
- 
To compare safety as assessed by complications post-surgery and other adverse events up 
to month 24 post-implantation visit between all coated and uncoated implants  
- 
To compare survival rate up to 24 months between all coated and uncoated implants for the 
groups  and all implants  
- 
To compare change in marginal bone height from day 1 to month 12 and 24 between all 
coated and uncoated implant for the  groups and all  implants 
- 
To compare frequency of peri-implantitis between coated and uncoated implant for the  
groups and all implants 
 
10.3 Hypotheses 
It is anticipated that there will be improved early change in stability observed with the coated 
compared to the uncoated implants, determined with change in ISQ highest values from day 1 to 12 
weeks after insertion. See Statistics section for further details.   

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11 Design of the clinical investigation 
This is a randomised, multicentre double-blind, parallel study where subjects will be randomised to 
receive coated or uncoated dental implant screws.  Subjects will be assessed during the 12 weeks’ 
post-operative period with an extended Post follow-up period up to 24 months after implantation. 
11.1 Primary and secondary endpoints 
11.1.1 Primary efficacy endpoint 
The primary endpoint is change in stability from day 1 to 12 weeks after implantation of the “index 
implant” comparing coated and uncoated implants. This will be assessed in terms of induced micro 
motion of the implant using the Osstell device. The ISQ values are recorded from two directions. The 
directions should be bucco-lingual and mesio-distal, whereof highest value of the two 
measurements will be used.  
11.1.2 Secondary efficacy endpoints for Part I: 
- 
Absolute ISQ highest value at week 8 and week 12 after implantation for “index implant” 
- 
Incidence of post-surgery complications and adverse events up to week 12 post-
implantation visit 
- 
Change in ISQ highest value from day 1 to 8 weeks for the “index implant”  
- 
Change in marginal bone height from day 1 to week 8 and 12 for the “index implant” 
- 
Absolute ISQ highest value at week 8 and 12 for all implants 
- 
Change in marginal bone height from day 1 to week 8 and 12 for all implants 
 
11.1.3 The secondary efficacy endpoints Part II are: 
- 
Post-surgical complications and other adverse events up to month 24 post-implantation visit  
- 
Survival rate up to 24 months for all implants 
- 
Change in marginal bone height from day 1 to month 12 and month 24 for all  implants 
- 
Occurrence of signs and symptoms with peri-implantitis at month 12 and month 24 for all 
implants 
 
12 Investigational device treatment  
12.1 Description of the device technique to be used 
The dental implants used in this study are of a typical generic design but without the CE mark. The 
devices are produced by Elos Medtech Timmersdala AB, Sweden.  A single size 4 diameter by 10mm 
long external hex screw implant will be used in the study.  The devices are manufactured in medical 
grade pure titanium and comply with relevant ISO and ASTM Standards for dental implants. 
 
The implants will be placed using standard technique for one-stage procedure. The implants will 
have a healing abutment placed at first surgery but the implants will not be loaded directly with the 
prosthetic reconstruction. An instruction for the use of the surgical procedure is detailed in the IFU. 
Further detailed instructions for the use are given in the Investigator Brochure.  
 
 
12.2 Description of investigational devices 
12.2.1 Investigational Device – Zolidd One ExHex Dental Implant  
AddBIO is the legal manufacturer of the Zolidd coated One ExHex dental implant screw. 

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12.2.2 Comparator Device One ExHex 
Same design as the investigational device but uncoated dental implant screw. 
12.3  Description of equipment used for assessment during investigation 
Bitewings should be taken in the same direction and place each time. Therefore, creating and using a 
stent is preferable. No calibration of Osstell is needed, always chose the higher of the two values 
from each reading, without taking notice to direction. 
13 Study schedule, visits, procedures and assessments  
Subject enrolment will take approximately 9-12 months to complete. Each subject has a 12 week 
follow-up post-surgery for Part I and an additional 24 month for Part II. 
 
The study will consist of two parts (see figure below). Part I is the main study ending when all 
subjects have reached visit 5. The study will be evaluated and a Clinical Study Report (CSR) will be 
written for this part. The total time from baseline to visit 5 will be approximately 14 weeks. 
Part II of the study is a post-follow up study starting when the first subject has completed visit 5. The 
other subjects are included, on an ongoing basis, as they have completed visit 5. There will be a 
separate CSR written for Study Part II.  
 
The study Part I will begin with a baseline visit, visit 1, Informed consent procedure will take place. 
Provided the subject will give informed consent for both Study Part I and Study Part II the screening 
procedure starts. Subjects will undergo all screening and baseline assessment procedures including 
assessments of dental status to determine number of implants needed. Subjects who meet all the 
inclusion criteria and none of the exclusion criteria will be given a date for implant surgery within 
three weeks. The required number of implants will be ordered from the Study Distributor. 
 
At the implantation day, visit 2, eligibility will be re-checked before the surgery procedure starts. The 
subjects who still are eligible will enter the treatment and the implantation surgery is conducted. 
The first follow-up visit after implantation will take place week 2 post-surgery and the last follow-up 
visit in Study Part 1 will be at week 12. Any post-surgical complications and adverse events will be 
collected and recorded in the eCRF. On demand, depending on the outcome of the surgery, 
additional visits might occur. 
 
Study Part II, the Post Follow-up Study, consist of two visits, one at month 12 and another visit at 
month 24 post-surgery. Post-surgical complications and adverse events from Study Part I will be 
followed-up if not resolved previously. Safety, survival rate and marginal bone loss will be assessed 
and outcome recorded in the eCRF. Additional visits might occur depending on the status of the 
subjects.  
 
 
 
 
 
 
 
 
 
 
 
 
 

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Part I 
 
 
 
 
 
 
 
 
                        
Visit 1                    Visit 2 (surgery)     Visit 3                 Visit 4                  Visit 5 
 
 
Part II (post follow-up) 
 
 
 
 
              Visit 6                          Visit 7 
 
 
 
 
13.1 Study visits and Schedule of events 
 
13.1.1 Baseline, visit 1 
 
Subjects will be asked to participate in the investigation and read and sign Informed Consent Form 
(ICF).  After all questions has been answered and that the consent has been signed subject will be 
screened to ensure they meet all inclusion criteria and none of the exclusion criteria. If the subject 
meets all criteria they will be scheduled for surgery within 3 weeks with exception for subjects 
undergoing extraction of teeth. Investigator will schedule surgery as appropriate for these patients. 
 
The following information will be collected and recorded: 
- 
Demographics 
- 
Medical history 
- 
Concomitant medications 
- 
Pregnancy test (urine dip stick, fertile woman) 
- 
Dental Status 
• 
General oral examination to evaluate status of s status of soft tissues and pre-operative 
radiographic evaluation to assess bone quality1 and alveolar ridge height and confirm 
suitability for implantation.  
• 
Decayed Missed Filled Teeth (DMTF). 
• 
Details of existing fillings, periodontal status, extractions and caries requiring further 
dental intervention. 
• 
All teeth to be replaced as part of the treatment for this investigation will be selected 
and the ‘“index implant”’ i.e. the most posterior maxillary site will be identified for the 
primary evaluation, all other implants will be followed for secondary evaluation. 
 
Baseline 
Zolidd One 
ExHex 
uncoated 
One ExHex 
8 weeks 
12 weeks 
12 months 
24 months 
2 weeks  

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13.1.2 Surgery, visit 2 
 
Details of surgical technique performed at implantation of implants included, any deviation from the 
standard protocol must be documented in the eCRF together with the reason for deviation.  
  
The following information will be collected during surgery: 
- 
Change in dental status 
- 
Information about number of implants and locations 
- 
General surgery information 
- 
X-ray to assess bone height 
- 
Any adverse events and/or adverse device effects will be collected and reported in the right 
section in the eCRF 
- 
Any change in concomitant medication 
13.1.3 Week two post-surgery, visit 3 
 
Subject will return to clinic at week 2 post-surgery for follow-up and removal of stitches if placed 
 
The following information will be collected: 
- 
Post-operative complications and Adverse events 
- 
Any contacts/visits at site since surgery before this visit 3 
 
 
13.1.4 Week eight post-surgery, visit 4 
Subject will return to clinic at week 8 post-surgery for follow-up. 
 
The following information will be collected: 
- 
General oral examination and ISQ evaluation for all implants ” will be evaluated. 
- 
X-ray evaluation to assess bone height 
- 
Post-operative complications and Adverse events 
- 
Any changes of concomitant medication 
- 
Any contacts/visits at site since surgery before this visit 4 
 
The primary focus will be the ‘“index implant”’ but all implants will be evaluated. Details of any other 
dental interventions or significant changes in concurrent conditions and/ or medications will also be 
documented. 
 
13.1.5  Week twelve post-surgery, visit 5  
Subject will return to the clinic at week 12 post-surgery for Part 1 final assessments and start of the 
Prosthetic phase. 
 
 
The following information will be collected: 
- 
Change in dental status 
- 
General oral examination and ISQ evaluation for all implants   will be evaluated. 
- 
X-ray evaluation to assess bone height 
- 
Post-operative complications and Adverse event 
- 
Any changes of concomitant medication 
- 
Any contacts/visits at site since before this visit 5 

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The prosthetic device should be placed; including information on the type (single crowns or a bridge) 
will be recorded in the eCRF. This visit will end the Part 1 of the study and an analysis will take place. 
A new appointment will be scheduled for the Post-follow up Study at month 12. 
13.1.6 Post follow-up 12 month, visit 6, Study Part II 
Subjects will be asked to return to the clinic at 12 months’ post-surgery for follow-up of the 
implants(s). The primary focus will remain the ‘“index implant”’ but all implants will be evaluated 
 
The following information will be collected: 
- 
General oral examination for all implants, , will be evaluated. 
- 
X-ray evaluation to assess bone height 
- 
Survival rate of implants 
- 
Major dental interventions 
- 
Complications and Adverse event 
- 
Any changes of concomitant medication 
13.1.7 Post follow-up month 24 visit 7 
Subjects will be asked to return to the clinic at 24 months’ post -surgery for follow-up of the 
implants(s). The primary focus will remain the ‘“index implant”’ but all implants will be evaluated 
 
The following information will be collected: 
- 
General oral examination for all implants, , will be evaluated. 
- 
X-ray evaluation to assess bone height 
- 
Survival rate of implants 
- 
Major dental interventions 
- 
Complications and Adverse event 
- 
Any changes of concomitant medication 
 
 

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Table 1 Schedule of events; Study Part I and Study Part II 
 
 
Study Part I 
Study Part II 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
Day/month 
Baseline 
-60 to - 1 
days 
Day 1 
Surgery 
2 
weeks 
 
8  
weeks 
 
12 
weeks 
12 
month 
24 
month 
Assessment/event 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X1 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Concomitant 
medication 
X 
X 
 
X 
X 
X 
X 
Oral examination2 
X 
X 
 
X 
X 
X 
X 
Pre-surgery 
radiographics3 
X 
 
 
 
 
 
 
X-ray4 
 
X 
 
X 
X 
X 
X 
ISQ5 
 
X 
 
X 
X 
 
 
Surgery 
 
X 
 
 
 
 
 
Stitches removed 
 
 
X 
 
 
 
 
Adverse event 
 
X 
X 
X 
X 
X 
X 
End of Part 16 
 
 
 
 
X 
 
 
End of Part II6 
 
 
 
 
 
 
X 
 
1 Re-confirm inclusion and exclusion criteria 
2 Soft tissue and dental status and changes from previous visit 
3 Bone quality, ridge height and suitability for implantation and/or signs of loosening 
4 Marginal bone height and signs of loosening of integration 
5 ISQ examinations, higher value must be recorded 
6, if a subject discontinues before end of Part 1 (visit 4) and/or end of Part II (visit 6) a termination page must be filled in 
with the reason for the premature discontinuation 
14 Study population 
Approximately 70 subjects will be screened to ensure 62 subjects to be enrolled, 31 subjects in each 
study group. The study is planned to be conducted in 4 sites in Sweden. A complete list of 
participating sites will be filed in the ISF and SMF. 
14.1  Enrolment of subjects 
Subjects seeking or being referred to the selected clinics for treatment of edentulous area in the 
posterior region of the mouth, with at least one tooth to be replaced in the maxillary region, will be 
asked to participate in the clinical investigation. 
14.2 Informed consent procedures 
 
Informed consent must be obtained prior to the subject entering into the study and before any 
study related procedures are performed. In obtaining and documenting informed consent, the 
Investigator must comply with the applicable regulatory requirement(s) and adhere to the current 
versions of ISO 14155 GCP standard and the Declaration of Helsinki. The potential subject should be 
provided with a written and oral explanation of the study. It is the Investigators responsibility to 

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ensure that each study subject is fully informed about the nature of the study, its purpose, expected 
duration, procedures, the benefits and risks involved. Each study subject should also be informed of 
their right to withdraw from the study at any time without prejudice.  
 
The informed consent must be obtained by a medically qualified Investigator. Another site staff can 
assist in informing the subject. Subjects should be given ample time to ask questions to the 
Investigator. To properly document the informed consent process, the Investigator should record 
notes in the subject’s medical record, and both the Investigator who conducted the informed 
consent procedure and subject are required to sign and date the informed consent form. 
 
A copy of the signed and dated informed consent form should be given to the subject and the 
original form should be filed in the ISF. 
14.3  Subject screening and Subject identification logs 
Investigators must keep a record of all subjects who were considered for enrolment even if they 
were not subsequently found suitable for the investigation. This information is necessary to verify 
that the subject population was selected without bias. A screening log will be provided for the 
purpose. 
 
Subjects eligible for the treatment phase will be allocated a code number in connection with 
enrolment.  Investigators must keep a confidential ID list with the latest known address and contacts 
of all subjects enrolled into the study linking the code number to each subject´s full identity. 
14.3.1 Subjects inclusion procedures 
The 70 subjects planned to be screened and the 62 subjects to be enrolled in this study will be 
carefully evaluated that they meet all inclusion criteria and none of the exclusion criteria; this will be 
recorded in the eCRF and in the Subject’s clinical record. 
14.3.2 Inclusion criteria  
The subject is eligible for inclusion in the study if all of the following criteria are met: 
- 
Male or female subjects aged >18 years 
- 
Subjects should be willing to take part, able to understand the information given to them, 
and give written consent 
- 
Subject diagnosed with partial edentulism and who needs at least one dental implant in the 
posterior upper jaw i.e. premolars to first molar The same subject may also need implants in 
the posterior mandible (premolar to first molar region) 
14.3.3 Exclusion criteria 
The subject is not eligible for inclusion in the study if any of the following criteria are met: 
- 
Suspected to be immunocompromised or are taking immunosuppressant 
- 
Current participation in another clinical investigation or participation within the last 6 
months 
- 
Known sensitivity/allergies to any of the test materials or any of their ingredients, such as 
bisphosphonate, titanium or human fibrinogen 
- 
Significant current or past medical history of hepatic, renal, cardiac, pulmonary, digestive, 
haematological, neurological, or psychiatric disease, hypercalcaemia,  previous or ongoing 
malignancy in the head and neck region or uncontrolled diabetes type I which in the opinion 
of the Investigator, would compromise the safety of the subject or affect the outcome of the 
investigation   
- 
Pregnant and lactating females or those actively seeking to become pregnant in the next 3 
months 
- 
Previous (last 5 years) or ongoing Bisphosphonate or Denosumab treatment 

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- 
Significant marginal bone loss prior to implant insertion requiring bone grafting or bone graft 
substitute 
- 
Subject with extraction(s) performed in the position of implant placement within the last 2 
months 
- 
Subject with need of >6 implants or a full bridge 
- 
The final prosthetic construction in need of support from neighbouring teeth. 
- 
Known drug or alcohol abuse 
- 
Subject only need implant(s) in the posterior mandible region 
14.4 Prohibited concomitant therapy 
Extensive dental treatment during the study period which may interfere with the outcome of the 
investigated device is not allowed. If a subject need any of the follow interventions the monitor must 
be contacted. 
The following is not permitted:  
 
- 
Connecting the prosthetic reconstruction to neighbouring teeth. 
14.5 Premature termination  
Subjects will be made aware of their right to terminate involvement in this investigation at any time 
and for whatever reasons without affecting their right to further treatment and to an appropriate 
follow-up investigation.  
Subjects who are diagnosed and need to start treatment for osteoporosis will be excluded from the 
study prematurely. 
The reason for any withdrawal must be documented in the appropriate eCRF page. If a subject is 
withdrawn from the study, the Sponsor must be notified immediately. 
14.6 Termination or suspension of the study   
In the event that the investigation generates an excessive frequency of unanticipated adverse device 
events a premature termination or suspension of the study will be considered. Premature 
termination or suspension may be requested by the competent authority, ethics committee or the 
Sponsor at any time. 
 
In the event a study site does not comply with regulations, lack of recruitment or poor quality data 
the site will be prematurely closed. 
 
Any decisions to terminate or suspend the investigation early or to close a study site will be notified 
in writing to both to the Investigators, Regulatory authority and the relevant Ethics Committees.  
 
The Sponsor retains the right to terminate the investigation for non-safety reasons by giving an 
appropriate period of notice to all involved parties as per contractual agreements in the Clinical 
Study Agreement (CSA). 
 
15  Adverse Events/Adverse Device Effect, Serious Adverse 
Event/Serious Adverse Event Effect and Device Deficiencies  
 
15.1  Definition of Adverse events (AE) 
Adverse Events are defined as any untoward medical occurrence, unintended disease or injury or 
any untoward clinical signs (including abnormal laboratory finding), in subjects, users or other 
persons whether or not considered related to the investigational medical device. 
 
NOTE 1: This definition includes events related to the investigational device or the comparator. 

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NOTE 2: This definition includes related to the procedure involved. 
NOTE 3: For users or other persons, this definition is restricted to events related to Investigational 
medical device 
15.1.1 Adverse device effects (ADE) 
Adverse event related to the use of an investigational medical device. 
 
Note 1 This includes any adverse event resulting from insufficiencies or inadequacies in the 
instruction for use, the deployment, the implantation, the installation, the operation, or any 
malfunction of the investigational medical device. 
Note 2 This includes any event that is a result of a use error or intentional abnormal use of the 
investigational medical device. 
 
15.1.2 Serious adverse events (SAE) 
Adverse Event that: 
a. Leads to a death, injury  or permanent impairment to a body structure or body function 
b. Leads to a serious deterioration in the health of the subject, that either resulted in: 
1. a life-threatening illness or injury or  
2. a permanent impairment of a body structure or a body function, or 
3. in-patient hospitalisation or prolonged hospitalisation,  
4. in medical or surgical intervention to prevent life-threatening illness  
c. Leads to foetal distress, foetal death or a congenital abnormality or birth defect 
15.1.3 Pregnancy 
 
If women become pregnant during the study she must be excluded from further study related 
examinations and follow-up visits. 
The investigator should report all pregnancies within 24 hours of awareness to the sponsor.  
 The pregnant subject will be followed until the end of the pregnancy. The outcome of the pregnancy 
must be reported on the pregnancy report form. Any spontaneous abortion, stillbirth, birth 
defect/congenital anomaly, death or other serious infant condition must be reported and followed 
up as an SAE. 
 
15.1.4 Serious adverse device effects (SADE) 
Adverse device effect that has resulted in any of the  consequences characteristic of a serious 
adverse event. 
15.1.5 Unanticipated Serious adverse device effects (USADE) 
 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
 
Note: Anticipated serious adverse device effect (ASADE) is an effect which by nature, incidence, 
severity or outcome has been identified in the risk analysis report. 
 
 
 

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15.1.6 Device deficiencies (DD) 
Inadequacy of an investigational medical device related to its identity, quality, quality, reliability, 
safety or performance. This may include malfunctions, use error, or inadequacy in the information 
supplied by the manufacturer.  
15.1.7 Reporting of Adverse Events/Adverse Device Effects 
All subjects will be carefully monitored for the occurrence of AEs during the investigation period 
from the run-in to the completion of follow up.  The Clinical Investigator will collect AE information 
using non-leading questions such as “have you experienced any new health problems or worsening 
of existing conditions”. Events directly observed or spontaneously volunteered by subjects will also 
be recorded. 
Clearly related signs, symptoms and abnormal diagnostic procedure results should be grouped 
together and reported as a single diagnosis or syndrome whenever possible. 
All AEs including but not limited to events reported by the subject or reported in response to an 
open question by the Clinical Investigator or member of this team, which fall into any of the above 
definitions must be recorded as an AE in the eCRF and should include the following information. 
- 
Brief description of the event (diagnosis) 
- 
Start date (and time, if relevant) 
- 
Stop date (and time, if relevant) (or resolution) 
- 
Severity 
- 
Action taken regarding the medical device 
- 
Opinion on causality 
- 
Seriousness 
- 
Outcome 
 
Severity will be assessed using the following definitions: 
Mild 
Aware of sign or symptom, but easily tolerated. 
Moderate 
Discomfort enough to cause interference with usual activity. 
Severe 
Incapacitating with inability to work or do usual activity. 
 
The relationship to investigational device will be assessed by the Investigator using the following 
definitions: 
Not related 
Evidence exists that the adverse event definitely has a cause other than the 
investigational device (e.g. pre-existing condition or underlying disease, 
intercurrent illness, or concomitant medication) and does not meet any other 
criteria listed. 
Unlikely 
The relationship with use of the device seems not relevant and/or the event 
can be reasonably explained by another cause, but additional information may 
be obtained. 
Possibly related 
A temporal relationship exists between the event onset and use of 
investigational device.  Although the adverse event may appear unlikely to be 
related to the investigational device, it cannot be ruled out with certainty; and 
or the event cannot be readily explained by the subjects’ clinical state or 
concomitant therapies. 
Probably 
related 
A temporal relationship exists between the event onset and administration of 
investigational device, and appears with some degree of certainty to be related 
based on known mechanism of action of the device.  It cannot be readily 
explained by the subjects’ clinical state or concomitant therapies. 

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Causal 
relationship 
(Definitely 
related) 
Strong evidence exists that the investigational device caused the adverse event.  
There is a temporal relationship between the event onset and administration of 
the investigational device including user error.  There is strong mechanistic 
evidence that the event was caused by the investigational device.  The subject’s 
clinical state and concomitant therapies have been ruled out as a cause. 
 
Any AE’s that are possibly, probably or definitely related will be classified as ADE. 
15.2  Reportable events and Emergency contact details 
 
  
All serious events: 
• 
Any  SAE 
• 
 
• 
Any Device Deficiency(DD) that might have led to a SAE if ( a) suitable action had not been 
taken or b) intervention had not been made or c) if circumstances had been less fortunate 
• 
New finding/updates in relation to already reported events 
 
that occur during the investigation, including death, must be reported to the sponsor or it’s 
representative immediately (within one working day) but no later than 3 calendar days after 
investigators awareness of the event  
The reporting will be performed electronically via the eCRF (Viedoc TM). The site staff will log into 
Viedoc TM and enter all available information regarding the reportable even in the AE Log for the 
specific subject. As soon as the event is saved as “serious” in Viedoc TM, an email alert will 
immediately be sent to the medical Monitor and AddBIO. 
In case any additional documentation should be required, PCG will request this information from the 
study site. All reportable events must be followed until resolution or until the investigator assesses 
them as being under full control.  .  
In case the eCRF is out of order, or no internet access is available at the study site, the reportable 
event should be reported using a paper copy form, which will be available at the site and should be 
completed manually. The completed, signed and dated report should, within 24 hours, be faxed to: 
 
PCG Clinical Services AB 
Att: PCG Pharmacovigilance 
Fax number: +46 (0) 18 4444 823 
 
The study site should notify the local CRA via phone or email about the submission of the SAE report. 
As soon as the personnel have access to Viedoc TM, the SAE should be reported electronically as well 
 
Sponsor will follow the procedures for reportable events to the Competent Authority as outlined in 
MEDDEV 2.7/3 revsion 3 May 2015 and  must report to Competent Authority immediately, but no 
later than 2 calendar days after awareness for any event that is death, serious injury, or serious 
illness and that requires remedial action for subject, users or other person. 
Any other new finding/update, immediately, but no later than 7 calendar days following the date of 
awareness of the sponsor. 
 
 
15.2.1 Emergency contact sponsor 
 

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Irene Herrmann, DDS, PhD 
Consultant 
Södra Småskolevägen 41 
429 44 Särö 
 
+46 (0) 708 93 66 13 
 
Email: ireneeherrmann@hotmail.com 
 
16 Monitoring 
The Sponsor is responsible for selecting qualified clinical sites in this clinical investigation and to 
ensure the proper conduct of the clinical study at each site respectively. The sponsor’s personnel or 
authorized designee will monitor all clinical sites in a manner consistent with ISO 14155 GCP 
standard, applicable SOPs, health authority regulations and the clinical research standards adopted 
by the sponsor (legal manufacturer). Monitoring will be done at Interim Monitoring Visits 
throughout the study and a Site Closeout Visit.  
 
The Site Selection Visit will be performed to document that the site can perform the study according 
to the protocol. When EC and CA approval has been obtained a Site Initiation Visit will be planned to 
train all involved study staff.  
During the study Interim Monitoring Visits will be performed to ensure protocol compliance and 
data collection.   
Site Close-out Visit will be performed when all data has been collected and all queries have been 
resolved (after database lock). 
 
The monitor will at the visits and between the visits: 
- 
Provide information and ongoing support to the Investigator 
- 
Verify that facilities remain acceptable 
- 
Verify that the investigational team is adhering to the CIP, ISO 14155 GCP standard and 
applicable regulations   
- 
Verify completeness, accuracy and consistency of the data collected  
- 
Conduct source data verification, which will require direct access to all original records for 
each subject (e.g. medical records) 
 
The monitor will maintain a close contact with the study site between monitoring visits through 
letters, e-mail or telephone calls to clarify any issues and to ensure the study is being carried out 
according to plan and the CIP.  
 
Site management and monitoring are further specified in the Study Monitoring Plan (SMP) issued for 
this study. 
 
All documentation and correspondence pertaining to the investigation (source data, letters etc.) 
should be kept in accordance with ISO 14155 GCP standard. The monitor will issue reports from all 
visits that will be reviewed by AddBIO or designate. In these reports problems will be identified, and 
resolution by corrective action will be tracked and documented.  
 
The investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing the eCRFs are resolved.  
 
All formal monitoring visits and/or other communication between Sponsor, Monitor, Investigator, or 
any other regulatory body (Ethics, CA) will be documented in specified format as per sponsor 
procedures and kept in accordance with ISO 14155 GCP Standard.  
 

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Full details regarding site monitoring will be covered in a separate Site Monitoring Plan (SMP) 
document. 
 
16.1 Subject Records and Source Data 
Data may be recorded directly in the eCRF, which will then be considered as source data. This must 
be documented in the SMP before the study starts. 
The origin of source data in the investigation will be further specified in SMP (“Origin of Source 
Data”).  
It is the responsibility of the Clinical Investigator to record essential information in the medical 
records in accordance with national regulations and requirements, including: 
- 
Investigation code 
- 
Subject screening number and/or subject number 
- 
That informed consent for participating in the study was obtained 
- 
Diagnosis 
- 
All visits during the investigation period 
- 
All AEs/ADEs 
- 
All SAE/SADEs 
- 
All DD 
- 
Treatments and medications 
- 
The identification of the device 
- 
Location of Code envelopes 
 
The Clinical Investigator is responsible for ensuring the accuracy, completeness, legibility and 
timeliness of the data recorded in the eCRFs. Signed sections of eCRFs will be monitored and 
collected on a regular basis. 
16.2 Access to Source Data and Documentation 
The Clinical Investigator should guarantee access to source documents for the monitor and auditors 
as well as for inspection by appropriate regulatory agencies, and the EC, if required. 
17 Quality assurance 
AddBIO is responsible for independent quality assurance (QA) audits of the clinical investigation 
processes, if deemed needed. Audit of the investigation sites may be conducted to assess and help 
assure the compliance with ISO 14155 GCP Standard and applicable regulatory requirements. The 
sites may be subject to a QA audit by the Sponsor or its representatives, as well as inspected by 
Competent Authorities (CA) and Ethical Committees (EC). This implies that auditors/inspectors will 
have the right to inspect the study sites at any time during and/or after completion of the 
investigation and must have access to source documents, including subjects’ medical records. By 
participating and signing this CIP this the Investigator agrees to this requirement. 
18 Statistical considerations 
18.1  Statistical and analytical plans 
The principal features of the statistical analysis of the data are described in this section. A more 
technical and detailed elaboration of the principal features will be written in a separate statistical 
analysis plan (SAP) and is to be finalised prior to database lock Part I. When the investigation up to 
week 12 is completed and the data are assembled, a blinded review of the planned analysis in Part I 
at the clean file meeting will be carried out. The review will concern the definition of outliers, 
violators, and exclusion of subjects or data from the analysis sets. Decisions made in connection with 

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the review will be documented. The SAP will be reviewed and could be updated as a result of the 
review of the data. The database lock to Part I will contain only study variables measured up to and 
include visit week12. Tables, figures and CSR to Part I will be based on this first database lock. 
 
When study Part II is completed and the data are assembled, a new blinded review for Part II will be 
carried out at this second clean file meeting. The second database lock will be performed for Part II 
based on data after 12 weeks visit. The final CSR will be based on all locked data. 
18.2 General methodology  
The design of the study is a two parallel group design. The main efficacy analyses will be performed 
on the Intention-to-Treat (ITT) populations between the two groups. Complementary performance 
analyses will be performed on the Per Protocol (PP) population. See section 18.4 below. 
 
For comparison between the two randomized groups regarding “index implant”, Fisher’s non-
parametric permutation test will be used for continuous variables, Mantel-Haenszel chi-square test 
for ordered categorical variables, and Chi-square test for non-ordered categorical variables and 
Fisher’s exact test for dichotomous variables.  
For primary efficacy variables and for other important continuous efficacy variables the 95% 
confidence interval for the mean difference between the two groups will be obtained by inversion of 
Fisher’s non-parametric permutation test by means of simulation. 
 
For comparison between the two randomized groups regarding analysis of all teeth within subjects a 
mixed model with random effects analysis adjusting for within subject correlation will be used. 
 
 
If significant clinical relevant differences are found between the two randomised groups in 
important baseline variables, then complementary efficacy analyses will be performed adjusted for 
these variables. 
 
 
For comparison over time within randomized groups Fisher’s non-parametric permutation test for 
paired observations will be used for change in continuous and Sign test for change in ordered 
categorical variables or change in dichotomous variables. 
 
The distribution of the variables will be given as mean, SD, median, minimum and maximum for 
continuous variables and as number and percentages for categorical variables. 
 
Time to loss of implant will be described with Kaplan-Meier curves and analysed with Log-rank test 
between the two randomised groups. 
 
All significance tests will be two-sided and conducted at the 5% significance level. 
 
18.3 Statistical hypothesis 
Primary Objective – the hypothesis is that there will be improved early stability of the ‘“index 
implant”’ observed with the coated than with the uncoated implants, determined with change in ISQ 
values from day 1 to 12 weeks after insertion.  
 
Secondary Objectives – the hypothesis is that there will be improved early stability of the “index 
implant”” observed with the coated than with the uncoated implants, determined with change in 
ISQ values from day 1 to 8 weeks after insertion.  

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Furthermore– the hypothesis is that there will be improved early stability of all implants observed 
with the coated than with the uncoated implants, determined with change in ISQ values from day 1 
to week 8 and 12 after insertion and determined with ISQ values at week 8 and week 12. 
The hypothesis is also that there will be less marginal bone loss for coated compared to uncoated 
implants from implantation to week 8 and 12. 
At the post follow-up visits at month 12 and 24 it is anticipated that this difference will be greater in 
the maxillary teeth as mandibular bone is usually of better quality. At month 12 and 24 post follow-
up compare safety, survival rate and change in marginal bone height from implantation between 
coated and uncoated implants. 
18.4 Analyses Datasets (statistical populations) 
18.4.1 Intention to treat (ITT) population 
The ITT population will include all randomized subjects with at least one performance measurement 
after implantation. The final definition will be made at the clean-file meeting for Part I before the 
breaking the code. 
18.4.2 Per protocol (PP) population 
The Per Protocol population will include all subjects in the ITT-population without significant 
protocol violations. Subjects identified as protocol violators will be documented and agreed on at 
the clean-file meeting for Part I before the database lock for Part I. 
18.4.3 Safety population 
Safety population will include all subjects who have received at least one implant.   
18.5  Performance Analyses  
18.5.1 Primary efficacy analysis 
Primary efficacy analysis will be the comparison of change in ISQ highest value for coated implant 
with change in ISQ highest value for the uncoated implant on the “index implant” from day 1 to 12 
weeks visit with Fisher’s non-parametric permutation test on the ITT-population at significance level 
0.05. For primary efficacy variable the 95% confidence interval for the mean difference between the 
coated and the uncoated implants is obtained by inversion of Fisher’s non-parametric permutation 
test by means of simulation. 
If the 12 months ISQ highest values are missing Last observation carry forward (LOCF) will be used 
from 8 weeks. 
If significant differences are found between the two randomised groups in important baseline 
predictors a complementary primary efficacy analyses will be performed adjusted for these variables 
using analysis of covariance (ANCOVA). 
 
Sensitivity analyses will be performed for primary efficacy variable change in ISQ highest value from 
day 1 to week 12 between coated and uncoated implants with multiple imputations for missing 
values using analysis of variance for the unadjusted analysis and analyses of covariance for the 
adjusted analysis if needed. When using multiple imputations LOCF should not be applied. 
Complementary analyses between the two randomized groups of the primary efficacy variable will 
be done on the PP-population. 
Primary efficacy analysis will be presented per centre and a separate analysis will also be performed 
in order to study centre effect for primary variables. In case of few centres, centre will be analysed 
as fixed effect.  
 

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18.5.2 Secondary efficacy analyses Part I 
Secondary performance analyses for Part I will be the comparison will be the comparison between 
the two randomized groups regarding all the secondary performance variables given in section 
11.1.2 using the statistical methodology given in sections 18.2 above on the ITT-population. 
Complementary analyses between the two randomized groups of secondary performance variables 
will be done on the PP-population. 
18.5.3 Secondary efficacy analyses Part II 
Secondary performance analyses for part II will be the comparison will be the comparison between 
the two randomized groups regarding all the secondary performance variables given in section 
11.1.3 using the statistical methodology given in sections 18.2 above on the ITT-population. 
Complementary analyses between the two randomized groups of secondary performance variables 
will be done on the PP-population. 
 
18.5.4 Exploratory performance analyses 
Univariable and multivariable analyses of baseline predictors to primary and selected secondary 
outcome variables will be performed using linear and/or logistic univariable regression analyses 
followed by forward stepwise multivariable linear and/or logistic regression analyses. 
18.6 Safety analysis 
Adverse events (AE) will be listed and summarised by body system, incidence, severity, seriousness 
and duration/outcome. All AE’s will be coded with MedDRA dictionary and tabulated by Preferred 
Term (PT) code and System Organ Class (SOC) code.  Serious Adverse Events (SAEs) or Serious 
Adverse Device Effects (SADEs) will be summarised separately.  Any premature discontinuations due 
to adverse events and deaths will be listed and summarised by treatment group.   
 
Time to loss of implant will be described with Kaplan-Meier curves and analysed with Log-rank test 
between the two randomised groups. 
 
All safety analyses will be performed on the safety population. 
18.7 Analysis of baseline variables 
All baseline variables will be tabulated by randomised group and analysed by randomised group 
according to the statistical methods given in the statistical methods given in section 18.2 above on 
both the ITT population and PP population. 
18.8 Determination of sample size 
The power analysis based on Abtahi et al. 2012:  The SD for change in ISQ value from placement to 
month 6 was 5.3 in the active group and 5.4 in the control group.  In order to be able to find a clinical 
difference of five ISQ highest values in change between placement and 12 weeks between the 
coated and the uncoated group with Fisher’s non-parametric permutation test with 90% power 28 
evaluable subjects are needed in each group assuming a SD for change in ISQ in each group of 5.6 
and a significance level 0.05. Thirty-one subjects will be randomized to each study group to 
compensate for 10% drop-out.  A total of 62 subjects will be randomized to the two groups. 
18.9 Randomisation procedure 
Subjects will be randomised in proportions 1:1 to receive either coated or uncoated screw implants.  
This will be in a balanced block design; the sequences and sizes of blocks may also be randomised.  
The aim being to maintain a balance in subject numbers across all centres in the investigation at any 
one time, provided recruitment rates are similar. 
 

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Once generated the central randomisation schedule will be kept blinded for the study monitor, 
investigators and data management staff. After un-blinding for analyses of Part I the study monitor 
and investigator should still be blinded regarding study patients. 
 
Coated implants batches will be kept separate from uncoated batches and suitably labelled to allow 
easy identification prior to final packaging before sterilisation.  Placement in final packaging and 
labelling with standard labels including Subject ID Number will be supervised and double checked.  
Further details of this process are included in the Investigator brochure as is the procedure for 
emergency code breaking. 
18.10 Expected drop-out rates 
It is anticipated that the dropout rate for this investigation should be low and based on previous 
work a dropout rate of less than 5% would be expected. The above figures include sufficient subjects 
to cover this margin. 
18.11 Interim analysis  
No interim analysis is planned. 
18.12 Reporting deviations from original statistics plan 
Deviation from original statistical plan will be specified in the statistical Analysis Plan (SAP). 
18.13 Sub-group analysis plans 
Interaction analyses will be performed between baseline variables and group effect, coated vs 
uncoated, regarding primary efficacy variable. 
Interactions effect with (p<0.10) will be followed by suitable subgroups analyses for that baseline 
variable. 
18.14 Handling missing or spurious data 
Last observation carry forward (LOCF) will be used from 8 weeks to 12 weeks in Part I and from 12 
months to 24 months in Part II. For primary efficacy analyses a sensitivity analysis will be performed 
with multiple imputations. 
18.15 Subject distribution in multicentre studies 
It is planned to include 3-4 clinics recruiting each approximately 5-20 subjects. 
19 Data management 
 
19.1 The web-based e-CRF 
Clinical data (including AEs and concomitant medications) will be entered into an eCRF (Viedoc™) 
provided by PCG. The eCRF includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. The 
data path – from data entry via the web interface over internet to storage in the database, and 
browsing over Internet - is fully validated by system design, testing and data validation. All the 
processes – development, testing, configuration, user training, staff training, support, and operation 
and disaster recovery – are fully validated in compliance with 21 CFR Part 11, ISO 14155, the Helsinki 
declaration and local medical and data protection acts.  Authorised trial site personnel designated by 
the Investigator will complete data collection. Appropriate training and security measures will be 
completed with the Investigator and all authorised trial site personnel prior to the trial being 
initiated and any data being entered into the system for any trial patient.  

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AddBIO will not have exclusive control of the trial data reported in the eCRF at any time. All data 
generated in the clinical trial relevant to the patients will be made under the control of the 
Investigator at all times during and after the trial. PCG will therefore ensure that a contemporaneous 
certified copy of the data will be created before PCG transfer the data to AddBIO and this certified 
copy must be retained at the Investigator site. The Investigator should be informed about the 
process. 
 
19.2 Data, database validation, query resolution, security and access 
All data will be reported in the eCRFs and/or diary cards either directly or from other Source 
Documents such as subject notes etc. At each site a Source Document Identification List must be 
completed by the responsible Investigator, prior to study start, to identify the location of source 
data and consequently enable the monitor to do a proper check of the eCRF entries against the 
source documents. The monitor should be fully aware of all source documents available at the site 
and verify site staff follows set procedures. 
 
eCRF’s will be reviewed during monitoring visits for data accuracy and completeness and where 
appropriate any outstanding data queries raised and resolved. eCRF data will be compared to source 
documents to ensure there are no discrepancies. All entries, corrections and alterations are to be 
made by the Investigator or designee in the e-CRF.  
 
Confidentiality of all data, especially subject sensitive data will be guaranteed through contractual 
obligations and professional standards of work practices by the clinical affairs and data management 
staff involved in this project. Subjects will be allocated a study number which will be entered on the 
eCRF. Only coded data will be transferred to the sponsor. Access to this data will be limited to those 
directly involved in the project and where data is stored it will be in a limited access environment 
both physically and electronically stored data being held securely and encrypted as appropriate. 
19.3 Data retention 
In line with the requirements of local regulations, the MDD 93/42/EEC and ISO 14155 the legal 
manufacturer will effectively retain the data from this investigation for 15 years after the lifetime of 
the device on the market. 
 
Investigators are obligated to retain the data as long as required by the local applicable regulation 
which usually is for 10 years after final signed CSR. Data include any original source documents 
related to the study, including the Subject Identification List, the original signed informed consent 
forms and detailed records of medical device use. AddBIO should be contacted before any study 
related documentation is planned for destruction. The data can be held at a third party secure 
location if required. 
19.4 Data QA procedures 
This study will be conducted in compliance with ISO 14155 GCP standard and any other local laws 
and/or regulations. AddBIO CLINSOPs apply unless other SOPs held by selected CRO are agreed. 
When other SOPs will be used they will be detailed in the contract with the selected CRO and 
AddBIO.   
20 Amendments to the clinical investigation plan 
Investigator may not amend the protocol without prior written permission of the Sponsor. If the CIP 
needs to be amended, the amendment must be agreed by both the sponsor and the investigators 
and approved by regulatory authority and by the ethics committee before implementation. Approval 
must also be obtained for updates to the written informed consent, when applicable.  

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An exception to above is a change of CIP procedures to eliminate immediate hazards to the study 
subject. 
21 Clinical investigation plan deviations 
 
Every effort should be made to comply with the requirements of the protocol.  Prior approval by the 
Sponsor is required for changes in or deviations from the CIP, except in an emergency.  If the 
changes or deviations may affect the rights, safety, or welfare of participants, IRB/IEC approval is 
required. Deviations will be recorded with an explanation for the change. The Sponsor is responsible 
for analysing the deviations and assessing their significance.  Corrective action will be implemented 
to avoid repeat deviations.   
Repeated and serious failures in Investigators or subject compliance will need to be addressed 
severely as they have the potential to affect both subject safety and investigation outcome. Refer to 
Section 14.6. 
 
 
 
 
 
 
22 Device accountability procedures and storage 
Accurate device accountability is an important and key element of the Sponsor’s ability and 
obligation to be able to trace all investigational devices used in a clinical investigation. AddBIO will 
ensure records are kept to document the location of all investigational devices from shipment to site 
until return and destruction. The site will be supplied with Accountability Logs which must be 
continuously updated by the site staff.  
The Investigator is responsible for ensuring the accountability logs received from the sponsor are 
accurately maintained. The logs must accurately reflect the accountability of the device product at 
all time. The site monitor will review these during monitoring visits. 
 All investigational products should be stored in an appropriate securely locked room with limited 
access at the trial sites.  
All material supplied is for use only in this clinical investigation and should not be used for any other 
purpose. At the end of the investigation, the remaining investigational devices will be returned to 
the sponsor after the conclusion of the study. 
23 Statement of compliance 
23.1 Relevant ethical and regulatory standards and guidelines 
The investigation will be conducted under the terms of the current versions of Declaration of 
Helsinki, and ISO 14155 Clinical investigation of medical devices for human subjects -- Good clinical 
practice.  The investigation will also follow the requirements of the appropriate annexes of MDD 
93/42/EEC. 
 
Regulatory authority and Ethics Committee approval must be in place prior to start the study. 

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23.2 Clinical indemnity insurance provision 
The Sponsor will maintain insurance coverage for the duration of the investigation as required by 
applicable local regulations. All relevant documentation regarding such insurance will be filed in the 
Study Master File and at each site as appropriate (ISF). 
24 Publication policy 
Once the study is approved and before the initiation the investigation will be notified to one of the 
appropriate clinical investigation databases in compliance with Declaration of Helsinki and 
publication policies. 
 
After completion of the study, a Clinical Investigation Report will be prepared and reported 
according to ISO 14155 GCP standard. Key results will be made publicly accessible. 
 
Publication policy will follow Declaration of Helsinki.  Negative and inconclusive as well as positive 
results will be published or otherwise made publicly available. Sources of funding, institutional 
affiliations and conflicts of interest will be declared in the publication.  
 
Prior to submitting for publication, presenting, using for instructional purposes, or otherwise 
disclosing the results of the investigation, the investigator agrees to allow AddBIO a period of at least 
30 days (or, for abstracts, at least 10 working days) to review the proposed publication or disclosure 
prior to its submission for publication or other disclosure.   
 
For this multicentre study, the first publication or disclosure shall be a complete, joint multicentre 
publication or disclosure.  This statement does not give AddBIO any editorial rights over the content 
of a publication or disclosure, other than to restrict the disclosure of AddBIO proprietary confidential 
information.   
 
 
 

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25 List of references 
 
1. 
Lekholm U, Zarb GA. Patient selection and preparation. In: Brånemark PI, Lekholm U, Zarb 
GA, Albrektsson T (eds). Tissue integrated Prostheses: Osseointegration in clinical dentistry. 
Chicago: Quintessence; 199-209. 
 
2. 
 Adell R, Lekholm U, Rockler B, Brånemark PI. A 15-year study of osseointegrated implants in 
the treatment of the edentulous jaw. Int J Oral Surg. 1981 Dec; 10(6):387-416. PubMed 
PMID: 6809663. 
 
3. 
 Lekholm U, Gröndahl K, Jemt T. Outcome of oral implant treatment in partially edentulous 
jaws followed 20 years in clinical function. Clin Implant Dent Relat Res. 2006; 8(4):178-86. 
PubMed PMID: 17100743. 
 
4. 
 Chiapasco M, Abati S, Romeo E, Vogel G. Implant-retained mandibular overdentures with 
Brånemark System MKII implants: a prospective comparative study between delayed and 
immediate loading. Int J Oral Maxillofac Implants. 2001 Jul-Aug; 16(4):537-46. PubMed 
PMID: 11516001. 
 
5. 
 Olsson, M., et al., MkII--a modified self-tapping Brånemark implant: 3-year results of a 
controlled prospective pilot study. Int J Oral Maxillofac Implants, 1995. 10(1): p. 15-21. 
 
6. 
 Whetman J, Mealey BL. Effect of Healing Time on New Bone Formation After Tooth 
Extraction and Ridge Preservation With Demineralized Freeze-Dried Bone Allograft: A 
Randomized Controlled Clinical Trial. J Periodontol. 2016 Sep; 87(9):1022-9. doi: 
10.1902/jop.2016.160139. PubMed PMID: 27133791. 
 
7. 
 Merli M, Moscatelli M, Mariotti G, Pagliaro U, Raffaelli E, Nieri M. Comparing membranes 
and bone substitutes in a one-stage procedure for horizontal bone augmentation. A double-
blind randomised controlled trial. Eur J Oral Implantol. 2015 Autumn; 8(3):271-81. PubMed 
PMID: 26355171. 
 
8. 
 Lindgren C, Mordenfeld A, Hallman M. A prospective 1-year clinical and radiographic study 
of implants placed after maxillary sinus floor augmentation with synthetic biphasic calcium 
phosphate or deproteinized bovine bone. Clin Implant Dent Relat Res. 2012 Mar; 14(1):41-
50. doi:10.1111/j.1708-8208.2010.00224.x. PubMed PMID: 20491816. 
 
9. 
 Felice P, Soardi E, Pellegrino G, Pistilli R, Marchetti C, Gessaroli M, Esposito M. Treatment of 
the atrophic edentulous maxilla: short implants versus bone augmentation for placing longer 
implants. Five-month post-loading results of a pilot randomised controlled trial. Eur J Oral 
Implantol. 2011Autumn; 4(3):191-202. PubMed PMID: 22043464. 
 
10. 
 Johansson LA, Isaksson S, Lindh C, Becktor JP, Sennerby L. Maxillary sinus floor 
augmentation and simultaneous implant placement using locally harvested autogenous 
bone chips and bone debris: a prospective clinical study. J Oral Maxillofac Surg. 2010 Apr; 
68(4):837-44. doi: 10.1016/j.joms.2009.07.093. PubMed PMID: 20307768. 
 
11. 
 Javed F, Vohra F, Zafar S, Almas K. Significance of osteogenic surface coatings on implants to 

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enhance osseointegration under osteoporotic-like conditions. Implant Dent. 2014 Dec; 
23(6):679-86. doi:10.1097/ID.0000000000000161. Review. PubMed PMID: 25290281. 
 
12. 
Abtahi J, Agholme F, Sandberg O, Aspenberg P. Effect of local vs. systemic bisphosphonate 
delivery on dental implant fixation in a model of osteonecrosis of the jaw. J Dent Res. 2013 
Mar; 92(3):279-83. doi: 10.1177/0022034512472335. PubMed PMID: 23264610. 
 
13. 
 AbtahiJ, Tengvall P, Aspenberg P.A bisphosphonate-coating improves the fixation of metal 
implants in human bone. A randomized trial of dental implants. May 2012Volume 50, Issue 
5, Pages 1148–1151 
 
14. 
 Abtahi J, Henefalk G, Aspenberg P. Randomised trial of bisphosphonate-coated dental 
implants: Radiographic follow-up after five years of loading. Int J Oral Maxillofac Surg. 2016 
Dec;45(12):1564-1569 
 
15. 
 Friberg B, Sennerby L, Linden B, Gröndahl K, Lekholm U. Stability measurements of one-
stage Brånemark implants during healing in mandibles. A clinical resonance frequency 
analysis study. Int J Oral Maxillofac Surg. 1999 Aug; 28(4):266-72. PubMed PMID: 10416893 
 
16. 
 Scarano A, Degidi M, Iezzi G, Petrone G, Piattelli A. Correlation between implant stability 
quotient and bone-implant contact: a retrospective histological and histomorphometrical 
study of seven titanium implants retrieved from humans. Clin Implant Dent Relat Res. 2006; 
8(4):218-22. PubMed PMID: 17100747 
 
17. 
 Barewal RM, Oates TW, Meredith N, Cochran DL. Resonance frequency measurement of 
implant stability in vivo on implants with a sandblasted and acid-etched surface. Int J Oral 
Maxillofac Implants. 2003 Sep-Oct; 18(5):641-51. PubMed PMID:  14579951 
 
18. 
 Trisi P, Carlesi T, Colagiovanni M, Perfetti G Implant Stability Quotient (ISQ) vs direct in-vitro 
measurement of primary stability (micro motion): effect of bone density and insertion 
torque J Osteol Biomat 2010; 1:141-151 | ID:-354 | 
 
19. 
 Pagliani L (L) ; Sennerby L (L) ; Petersson A (A) ; Verrocchi D (D) ; Volpe S (S) ; et al. 
The relationship between resonance frequency analysis (RFA) and lateral displacement of 
dental implants: an in vitro study. J Oral Rehabil ; 2013-Mar ; 40(3):221-7  
 
20. 
 Simunek A, Kopecka D, Brazda T, Strnad I, Capek L, Slezak R. Development of implant 
stability during early healing of immediately loaded implants. Int J Oral Maxillofac Implants. 
2012 May-Jun; 27(3):619-27. PubMed PMID: 22616056. 
 
21. 
 Ersanli S, Karabuda C, Beck F, Leblebicioglu B. Resonance frequency analysis of one-stage 
dental implant stability during the osseointegration period. J Periodontol. 2005 Jul; 
76(7):1066-71. PubMed PMID: 16018748 
 
22. 
 Sennerby L, Meredith N. Resonance frequency analysis: measuring implant stability and 
osseointegration. Compend Contin Educ Dent. 1998 May; 19(5):493-8, 500, 502; quiz 504. 
PubMed PMID: 9693511. 
 
23. 
 Roos J, Sennerby L, Lekholm U, Jemt T, Gröndahl K, Albrektsson T. A qualitative and 
quantitative method for evaluating implant success: a 5-year retrospective analysis of the 
Brånemark implant. Int J Oral Maxillofac Implants.  1997 Jul-Aug; 12(4):504-14. PubMed 

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PMID: 9274079. 
 
24. 
 Friberg B, Jemt T. Rehabilitation of edentulous mandibles by means of osseointegrated 
implants: a 5-year follow-up study on one or two-stage surgery, number of implants, 
implants surfaces, and age at surgery. Clin Implant Dent RelatRes. 2015 Jun; 17(3):413-24. 
doi: 10.1111/cid.12116. PubMed PMID: 23879577. 
 
25. 
 Eliasson A, Narby B, Ekstrand K, Hirsch J, Johansson A, Wennerberg A. A 5-year prospective 
clinical study of submerged and nonsubmerged Paragon system implants in the edentulous 
mandible. Int J Prosthodont. 2010 May-Jun; 23(3):231-8. PubMed PMID: 20552088. 
 
30. 
 Sanz M, Ivanoff CJ, Weingart D, Wiltfang J, Gahlert M, Cordaro L, Ganeles J, Bragger U, 
Jackowski J, Martin WC, Jung RE, Chen S, Hammerle C. Clinical and radiologic outcomes after 
submerged and transmucosal implant placement with two-piece implants in the anterior 
maxilla and mandible: 3-year results of a randomized controlled clinical trial. Clin Implant 
Dent Relat Res. 2015 Apr; 17(2):234-46. doi: 10.1111/cid.12107. PubMed PMID: 23837502. 
 
31. 
 Wermelin, K., P. Tengvall, and P. Aspenberg, Surface-bound bisphosphonates enhance screw 
fixation in rats--increasing effect up to 8 weeks after insertion. Acta Orthop, 2007. 78(3): p. 
385-92. 
 
32. 
 Toksvig-Larsen, S. and P. Aspenberg, Bisphosphonate-coated external fixation pins appear 
similar to hydroxyapatite-coated pins in the tibial metaphysis and to uncoated pins in the 
shaft. Acta Orthop, 2013. 84(3): p. 314-8. 
 
33. 
 Wermelin, K., et al., Bisphosphonate coating on titanium screws increases mechanical 
fixation in rat tibia after two weeks. J Biomed Mater Res A, 2008. 86(1): p. 220-7. 
 
34. 
 Dhillon, S., Zoledronic Acid (Reclast(®), Aclasta(®)): A Review in Osteoporosis. Drugs, 2016. 
76(17): p. 1683-1697. 
 
35. 
 Solomon, C., et al., Safety of fibrinogen concentrate: analysis of more than 27 years of 
pharmacovigilance data. Thromb Haemost, 2015. 113(4): p. 759-71. 
 
36. 
A Walter C, Al-Nawas B, Wolff T, Schiegnitz E, Grötz KA. Dental implants in patients treated 
with antiresorptive medication - a systematic literature review. Int J Implant Dent. 2016 Dec; 
2(1):9. Review. PubMed PMID: 27747701; PubMed Central PMCID: PMC5005701. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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26 APPENDICES 
 
26.1  Appendix I Declaration of Helsinki 
 
World Medical Association - Declaration of Helsinki - Ethical Principles for 
Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the:  
29th WMA General Assembly, Tokyo, Japan, October 1975  
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989  
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification 
added)  
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)  
59th WMA General Assembly, Seoul, Republic of Korea, October 2008  
64th WMA General Assembly, Fortaleza, Brazil, October 2013  
 
Preamble  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as 
a statement of ethical principles for medical research involving human subjects, 
including research on identifiable human material and data. The Declaration is 
intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs.  
 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research 
involving human subjects to adopt these principles.  
 
General Principles  
3. The Declaration of Geneva of the WMA binds the physician with the words, “The 
health of my patient will be my first consideration,” and the International Code of 
Medical Ethics declares that, “A physician shall act in the patient's best interest when 
providing medical care.”  
 
4. It is the duty of the physician to promote and safeguard the health, well-being and 
rights of patients, including those who are involved in medical research. The 
physician's knowledge and conscience are dedicated to the fulfilment of this duty.  
 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects.  
 

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6. The primary purpose of medical research involving human subjects is to understand 
the causes, development and effects of diseases and improve preventive, diagnostic 
and therapeutic interventions (methods, procedures and treatments). Even the best 
proven interventions must be evaluated continually through research for their 
safety, effectiveness, efficiency, accessibility and quality.  
 
7. Medical research is subject to ethical standards that promote and ensure respect for 
all human subjects and protect their health and rights.  
 
8. While the primary purpose of medical research is to generate new knowledge, this 
goal can never take precedence over the rights and interests of individual research 
subjects.  
 
9. It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
personal information of research subjects. The responsibility for the protection of 
research subjects must always rest with the physician or other health care 
professionals and never with the research subjects, even though they have given 
consent.  
 
10.  Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or 
regulatory requirement should reduce or eliminate any of the protections for 
research subjects set forth in this Declaration.  
 
11.  Medical research should be conducted in a manner that minimises possible harm to 
the environment.  
 
12.  Medical research involving human subjects must be conducted only by individuals 
with the appropriate ethics and scientific education, training and qualifications. 
Research on patients or healthy volunteers requires the supervision of a competent 
and appropriately qualified physician or other health care professional. 
 
13.  Groups that are underrepresented in medical research should be provided 
appropriate access to participation in research.  
 
14.  Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients 
who serve as research subjects.  
 
15.  Appropriate compensation and treatment for subjects who are harmed as a result 
of participating in research must be ensured.  
 
 

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Risks, Burdens and Benefits  
16.  In medical practice and in medical research, most interventions involve risks and 
burdens. Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the risks and burdens to the research 
subjects.  
 
17.  All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups involved 
in the research in comparison with foreseeable benefits to them and to other 
individuals or groups affected by the condition under investigation. Measures to 
minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher.  
 
18. Physicians may not be involved in a research study involving human subjects unless 
they are confident that the risks have been adequately assessed and can be 
satisfactorily managed. When the risks are found to outweigh the potential benefits 
or when there is conclusive proof of definitive outcomes, physicians must assess 
whether to continue, modify or immediately stop the study. 
 
 Vulnerable Groups and Individuals  
 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. All vulnerable groups 
and individuals should receive specifically considered protection.  
 
20. Medical research with a vulnerable group is only justified if the research is 
responsive to the health needs or priorities of this group and the research cannot be 
carried out in a non-vulnerable group. In addition, this group should stand to benefit 
from the knowledge, practices or interventions that result from the research.  
 
Scientific Requirements and Research Protocols  
21. Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, 
other relevant sources of information, and adequate laboratory and, as appropriate, 
animal experimentation. The welfare of animals used for research must be 
respected.  
 
22. The design and performance of each research study involving human subjects must 
be clearly described and justified in a research protocol. The protocol should contain 
a statement of the ethical considerations involved and should indicate how the 
principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, potential conflicts 
of interest, incentives for subjects and information regarding provisions for treating 
and/or compensating subjects who are harmed as a consequence of participation in 

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the research study. In clinical trials, the protocol must also describe appropriate 
arrangements for post-trial provisions.  
 
Research Ethics Committees  
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the 
researcher, the sponsor and any other undue influence and must be duly qualified. It 
must take into consideration the laws and regulations of the country or countries in 
which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. The committee must 
have the right to monitor ongoing studies. The researcher must provide monitoring 
information to the committee, especially information about any serious adverse 
events. No amendment to the protocol may be made without consideration and 
approval by the committee. After the end of the study, the researchers must submit 
a final report to the committee containing a summary of the study’s findings and 
conclusions.  
 
Privacy and Confidentiality  
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information.  
 
Informed Consent  
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family 
members or community leaders, no individual capable of giving informed consent 
may be enrolled in a research study unless he or she freely agrees.  
 
26. In medical research involving human subjects capable of giving informed consent, 
each potential subject must be adequately informed of the aims, methods, sources 
of funding, any possible conflicts of interest, institutional affiliations of the 
researcher, the anticipated benefits and potential risks of the study and the 
discomfort it may entail, post-study provisions and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in 
the study or to withdraw consent to participate at any time without reprisal. Special 
attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. After ensuring 
that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given 
informed consent, preferably in writing. If the consent cannot be expressed in 
writing, the non-written consent must be formally documented and witnessed. All 
medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
 
27. When seeking informed consent for participation in a research study the physician 
must be particularly cautious if the potential subject is in a dependent relationship 

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with the physician or may consent under duress. In such situations the informed 
consent must be sought by an appropriately qualified individual who is completely 
independent of this relationship.  
 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. 
These individuals must not be included in a research study that has no likelihood of 
benefit for them unless it is intended to promote the health of the group 
represented by the potential subject, the research cannot instead be performed with 
persons capable of providing informed consent, and the research entails only 
minimal risk and minimal burden.  
 
29. When a potential research subject who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the 
physician must seek that assent in addition to the consent of the legally authorised 
representative. The potential subject’s dissent should be respected.  
 
30. Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or 
mental condition that prevents giving informed consent is a necessary characteristic 
of the research group. In such circumstances the physician must seek informed 
consent from the legally authorised representative. If no such representative is 
available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a 
condition that renders them unable to give informed consent have been stated in 
the research protocol and the study has been approved by a research ethics 
committee. Consent to remain in the research must be obtained as soon as possible 
from the subject or a legally authorised representative.  
 
31. The physician must fully inform the patient which aspects of their care are related to 
the research. The refusal of a patient to participate in a study or the patient’s 
decision to withdraw from the study must never adversely affect the patient-
physician relationship.  
 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
 
Use of Placebo  
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following 
circumstances: Where no proven intervention exists, the use of placebo, or no 
intervention, is acceptable; or Where for compelling and scientifically sound 
methodological reasons the use of any intervention less effective than the best 

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proven one, the use of placebo, or no intervention is necessary to determine the 
efficacy or safety of an intervention and the patients who receive any intervention 
less effective than the best proven one, placebo, or no intervention will not be 
subject to additional risks of serious or irreversible harm as a result of not receiving 
the best proven intervention. Extreme care must be taken to avoid abuse of this 
option.  
 
Post-Trial Provisions  
34. In advance of a clinical trial, sponsors, researchers and host country governments 
should make provisions for post-trial access for all participants who still need an 
intervention identified as beneficial in the trial. This information must also be 
disclosed to participants during the informed consent process.  
 
Research Registration and Publication and Dissemination of Results  
35. Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations 
with regard to the publication and dissemination of the results of research. 
Researchers have a duty to make publicly available the results of their research on 
human subjects and are accountable for the completeness and accuracy of their 
reports. All parties should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results must be published or otherwise 
made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication. Reports of research not in accordance 
with the principles of this Declaration should not be accepted for publication.  
 
Unproven Interventions in Clinical Practice  
37. In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions have been ineffective, the physician, after seeking expert 
advice, with informed consent from the patient or a legally authorised 
representative, may use an unproven intervention if in the physician's judgement it 
offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to 
evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available. 
 
 
 
 
 

Clinical Investigation Plan 
 
Sponsor: AddBIO 
Version: Final Version 3 
 
CIP code: ADD-001 
Date: 2017-07-14 
 
 
 
 
Confidential 
50(53) 
 
 
 
26.2 Appendix 2 Instructions for Use  
 
 
 
Instructions for use Zolidd One ExHex – SE 
Date:  Revision 4 2017-04-28 
 
AddBIO AB, Teknikringen 10 
SE-583 30, Linköping 
 
 
 
Produktbeskrivning 
 
Zolidd One ExHex är ett dentalimplantat som tillhandahålls i två olika utföranden, dels obelagda och 
dels belagda med den bioaktiva beläggningen Zolidd. 
 
De belagda implantaten har belagts med ytan Zolidd för att påskynda inläkningen av implantatet, 
speciellt i områden med sämre benkvalitet. Zolidd består av ett nanolager humant blodprotein samt 
bisfosfonat. 
 
Implantatet är ett skruvformat titanimplantat (titan grad 4) av storlek Ø4.0x10mm med en 
marginalanpassning för R (reguljär 3,75 och 4mm) profil så kallad ”external hex design”. 
 
Implantatet är en generisk variation på Nobel Biocares originalimplantat designat av MkIV och därav 
kompatibelt med kirurgiska och protetiska komponenter för MkIV. 
 
Kompatibilitet 
 
Implantatet är kompatibelt med instrument, borr och protetiska komponenter från Nobel Biocare, 
enligt ad modum Brånemark. 
 
Indikationer  
Partiellt tandlöshet 
 
Varningar, försiktighetsåtgärder och kontraindikationer 
Samma generella försiktighetsåtgärder gäller som vid alla dentala implantatoperationer. 
 
Endast käkkirurger eller tandläkare med lång erfarenhet av att installera dentala implantat i enlighet 
med ad modum Brånemark skall använda AddBIOs implantat. 
 
Kända riskfaktorer inkluderar otillräcklig benvolym, infektion, otillräcklig mjukvävnad, okontrollerad 
diabetes, rökning, bruxism, ogynnsamma käkförhållanden, oro-facial strålbehandling, 
steroidbehandling, systemisk behandling med bisfosfonat samt cellgiftsbehandling. 
 
Patienter med allergier mot titan, zoledronat (bisfosfonat) eller andra bisfosfonater, eller fibrinogen- 
koncentrat bör inte behandlas med detta implantat. 

Clinical Investigation Plan 
 
Sponsor: AddBIO 
Version: Final Version 3 
 
CIP code: ADD-001 
Date: 2017-07-14 
 
 
 
 
Confidential 
51(53) 
 
Fibrinogen framställs från blod som kommer från bloddonatorer. Vid tillverkningen vidtas speciella 
åtgärder för att förhindra att infektioner överförs till patienter. Detta inkluderar ett noggrant urval av 
blod- och plasmagivare för att säkerställa att personer med risk för att vara smittbärare utesluts, samt 
test av enskilda donationer och plasmapooler för tecken på virus/infektion. Tillverkaren av läkemedlet 
inkluderar dessutom steg i hanteringen som kan inaktivera eller avskilja eventuella virus. Trots detta 
kan risken för överföring av infektion inte helt uteslutas när läkemedel framställda ur humant blod 
eller plasma ges. Detta gäller även okända eller nya virus och andra typer av infektioner. 
 
 
Implantatet är säkert vid MR undersökning men kan orsaka bildartefakter. 
 
 
 
 Sterilitet 
 
Implantaten tillhandahålls sterila. Om antingen implantatet eller förpackningen verkar skadade, om 
utgångsdatum passerat eller om steriliteten av något annat skäl ifrågasätts, ska implantatet inte 
användas. Produkten får inte återanvändas eller om-steriliseras då detta kan påverka ytbeläggningen 
negativt. 
 
 
 
Tillvägagångssätt 
 
1. Patienten förbereds för implantatoperation med en utvidgad medicinsk och oral undersökning. 
 
2. Benkvalitet och viktiga anatomiska strukturer fastställs med hjälp av lämpliga röntgenologiska 
utvärderingar i de tandlösa posteriora områdena. 
 
3. Vid operationstillfället skall området bedövas, vanligtvis med lokal bedövning. 
 
4. Tandköttet klaffas upp enligt implantatkirurgisk standardmodell. 
 
5. De fastställda implantatsätena (kan vara enstaka eller multipla) markeras med ett rundborr eller 
direkt med spiralborr. Därefter borras de med spiralborr med stigande storlek från ∅2.0x10mm 
till ”Twist step drill” ∅2.4/2.8 x10mm och ” ∅2.8/3.2 x10mm för de mjukaste kvaliteterna. När benet 
ger mer motstånd som i medium till hårt ben kan även ett ∅3.2/3.6 x10mm borr användas. Följ 
instruktionerna enligt IFU för MkIV. Max borrhastighet är 2000 varv/minut med adekvat NaCl 
spolning. 
 
Borrdjupet blir ca 1mm djupare än angiven markering på borret p.g.a. borrets spets, varför det krävs > 
2mm distans till närliggande anatomiska strukturer. 
 
6. Implantatsätet förgängas ej, och implantatet installeras med maxhastighet 25 varv/minut och med 
max 45 Ncm. När implantatet nått sitt rätta läge i sätet skall kirurgen manuellt känna att det är stabilt. 
ISQ skall användas för att mäta stabiliteten. 
 
7. En läkdistans sätts på implantatet och operationssåret sys ihop. 
 
8. Eventuella stygn tas bort efter ca 2 veckor 
 
 

Clinical Investigation Plan 
 
Sponsor: AddBIO 
Version: Final Version 3 
 
CIP code: ADD-001 
Date: 2017-07-14 
 
 
 
 
Confidential 
52(53) 
 
9. Implantationen sker enligt så kallad 1-stegsförfarande. Det vill säga att en läkdistans placeras på 
implantatet vid operationstillfället. Direkt belastning av implantatet skall undvikas under 
inläkningsperioden på 3 månader.  
 
10. Inför avtryckstagning avlägsnas först läkdistansen. Sedan skall ISQ mätas för att fastställa att 
stabiliteten är acceptabel. Har stabiliteten minskat i stället för ökat jämfört med det tidigare ISQ 
värdet bör förlängd inläkningstid övervägas. Är implantatet helt mobilt kan ett nytt implantat sättas i 
sätet. Avtryck för protetik sker efter att läkdistansen avlägsnats och enligt gängse förfarande med 
avtryckstagning med öppen sked först. Läkdistansen sätts tillbaka på plats igen till dess att det 
protetiska arbetet är klart och skall sättas på plats. 
 
11. Implantatavtrycket tillsammans med ett avtryck på motstående käke och en bitning skickas till 
tandtekniskt lab. för framställning av lämplig protetisk konstruktion. 
 
12. När protetiken är klar tas läkdistansen av och protetiken ansluts. Den protetiska 
(bro)konstruktionen skall passa passivt utan att någon kraft används när den skruvretineras på plats 
enlig ad modum Brånemark. 
 
13. Post-protetisk uppföljning sker enlig standardförfarande ad modum Brånemark med årlig oral 
undersökning och röntgen efter år 1 och 2 därefter med längre intervall. 
 
14. Patienten informeras om hur man håller rent kring sina ersättningar och om att utan dröjsmål 
kontakta behandlande tandläkare vid eventuella besvär.