Clinical and Health Economic Evaluation of a New Baha® Abutment, With a Minimally Invasive Surgical Technique. An International Multicentre, Open, Randomised, Comparative, Parallel Group, Investigation. 1y Investigation, 2y Follow-up
Phase: NA
Conditions: Deafness, Hearing Loss, Hearing Loss, Conductive, Hearing Loss, Mixed Conductive-Sensorineural
Sponsor: Cochlear Bone Anchored Solutions

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Clinical Investigation Plan (CIP) 
 
 
 
 
Investigation code  
CBAS5439 
Version  
Version date 
Final  
19-SEP-2013 
 
 
 
 
 
 
 
 
 Clinical and health economic evaluation with a new Baha®  
abutment design combined with a minimally invasive surgical 
technique  
 
An international multicentre, open, randomised, comparative, parallel group, prospective 
clinical investigation. 
1 year investigation with a 2 year follow-up 
. 
 
 
 
 
 
 
 
 
Co-ordinating investigator 
Professor Robert Stokroos  
 
Investigational site  
Department of Otorhinolaryngology 
Head and Neck Surgery 
University Hospital Maastricht 
Maastricht 
The Netherlands 
 
 
 
 
 
 
 
 
 
Sponsor  
Cochlear Bone Anchored Solutions AB  
Konstruktionsvägen 14 
PO Box 82 
SE-435 22 Mölnlycke 
Sweden 
 
 
 
 
 
 
 
 
This document contains trade secrets and confidential commercial information, disclosure of which is 
prohibited without providing advance notice to Cochlear and opportunity to object. 
 

 2 (44) 
 
 
 
Investigational sites 
Principal Investigator 
Professor Robert Stokroos Department of Otorhinolaryngology 
Head and Neck Surgery 
University Hospital Maastricht 
Maastricht 
The Netherlands 
 
Principal Investigator  
Mr. Ian Johnson 
Dept of ENT 
Freeman Hospital 
Newcastle upon Tyne 
NE7 7DN United Kingdom 
 
Principal Investigator  
Dr. Joacim Stalfors  
Sahlgrenska University Hospital 
ENT Clinic 
SE-413 45 Gothenburg 
Sweden  
 
A change to this section does not require a protocol amendment.  
 
Health Economist  
Associate Professor Manuela A. Joore  
Department of Clinical Epidemiology and Medical Technology Assessment 
Maastricht University Medical Center 
The Netherlands 
 
 
Clinical investigation management 
Director  
Mark Flynn 
Research & Applications   
Cochlear Bone Anchored Solutions 
Konstruktionsvägen 14, PO Box 82, 435 22 Mölnlycke 
Sweden 
Clinical Research Manager 
(CRM) 
Johan Blechert 
Clinical Research Manager 
Research & Applications 
Cochlear Bone Anchored Solutions 
Konstruktionsvägen 14, PO Box 82, 435 22 Mölnlycke 
Sweden 
Statistician 
 
Nils-Gunnar Pehrsson 
Senior Biostatistician 
Statistiska Konsultgruppen 
Thorild Wulffsgatan 1, SE-413 19 Göteborg  
Sweden 
Data manager  
 
Niklas Svensson 
Senior Data Manager 
dSharp Consulting 
Cahlmersgatan 3A, SE-411 35 Göteborg  
Sweden 
 
A change to this section does not require a protocol amendment.  

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Synopsis 
 
Name of sponsor  
 
Cochlear Bone Anchored Solutions AB  
Investigation code 
 
CBAS5439 
Investigational title 
 
Clinical and health economic evaluation with a new Baha 
abutment design combined with a minimally invasive surgical 
technique  
 
Design 
An international multicentre, open, randomised, comparative, parallel 
group, prospective clinical investigation.  
1 year investigation with a 2 year follow-up 
 
Investigational device(s)  
Cochlear Baha BA400 Abutment pre-mounted on Cochlear 
Baha BI300 4 mm implant 
 
Comparator(s) 
Cochlear Baha BA300 Abutment pre-mounted on Cochlear 
Baha BI300 4 mm implant 
 
Primary objectives  
 
To demonstrate that the minimally invasive surgical procedure in 
combination with the use of the BA400 abutment is associated 
with a reduction of inflammation/ infection, overgrowth, pain and 
numbness at the site of implantation compared to the traditional 
surgical procedure in combination with the use of the standard 
Baha abutment (Cochlear Baha BA300 Abutment). 
 
 
To demonstrate that the minimally invasive surgical procedure in 
combination with the use of the BA400 abutment is associated 
with a reduction in direct medical costs, due to shorter surgical 
procedures, faster wound healing and less complications 
compared to the traditional surgical procedure in combination with 
the use of the standard Baha abutment (Cochlear Baha BA300 
Abutment). 
 
 
Secondary objective(s)  
 
To demonstrate that the new surgical procedure and use of the 
BA400 in comparison with traditional surgical procedure and the 
use of BA300, is associated with: 
 
 
Less symptoms of inflammation and infection (Holgers 
index) 
 
Less tissue thickening/overgrowth  
 
Less pain  
 
Less numbness 
 
Faster wound healing  
 
Better aesthetic 
 
Shorter surgical procedures 
 
 
Safety evaluation (loss of implant, adverse events and device 
deficiency)  
 
 
 

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Tertiary objective  
To demonstrate that subjects experience an improved quality of life 
when receiving a Baha. 
 
Duration of subjects 
participation  
 
3 years  
Investigation period 
First Subject First Visit  
Q4 2012 
Last Subject  Last Visit  
  Q1 2017 
 
Inclusion criteria  
 
Adult patient, i.e. ≥ 18 years of age 
 
Eligible for the Baha system 
 
Signed informed consent 
 
Exclusion criteria  
 
Patient scheduled for simultaneously bilateral implant surgery  
 
Uncontrolled diabetes as judged by the investigator  
 
Condition that could jeopardize osseointegration and/or wound 
healing, e.g. osteoporosis, psoriasis and use of corticosteroids   
 
Unable to follow the cleaning instruction 
 
Unable to follow investigational procedures, e.g. to complete 
quality of life scales 
 
Participation in another investigation with pharmaceuticals and/or 
device 
 
Condition that may have an impact on the outcome of the 
investigation as judged by the investigator  
 
 
Suitable implant position for the 4 mm implant not found during 
surgery due to insufficient bone quality and/or bone thickness  
 
Number of subjects  
100 evaluable subjects  (in order to compensate for a drop-out rate of 
5%, 53 subjects  will be randomised to each treatment group). 
 
Randomisation in proportion 1:1 
 
Primary 
endpoint(s)/assessment(s)  
The first primary endpoint, a combined endpoint of 
infection/inflammation, overgrowth, pain and numbness,will be 
evaluated by a function of the Holgers Index, the Soft tissue 
thickening/over-growth scale, POSAS pain scale, question regarding 
pain in scar/neuropathic pain and Numbness scale. 
 
The second primary variable, the costs of the surgical procedure, 
complications and number of extra wound dressings sessions will be 
evaluated by surgical time, Holgers Index and the number of extra 
dressing sessions. The costs will be estimated and evaluated in local 
currency. 
 
Secondary 
endpoints/assessments 
 
Wound healing 
 
Numbness  
 
Pain  
 
Aesthetics 
 
Complications 
 
Overgrowth 
Quality of Life 

 5 (44) 
 
 
Safety variable(s) 
 
Loss of implant  
 
Adverse events  
 
Device deficiency 
 
Statistical methods 
The first combined primary variable will be analysed by the  Mantel- 
Haenszel Chi-square test and the cost by the Mann-Whitney U-test 
between the two groups 
 
 
Flow chart  - see below 

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Flow chart   
Procedures and timing  
Visit 1 
Baseline 
Visit 2 
Surgery 
 
Visit 
3 
Visit 
4 
Visit  
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit  
10 
Day/Week/Month1 
Before 
day of 
surgery 
 
D 
0 
D 
10 
W 
3 
W 
6 
W 
12 
W 
24 
M 
12 
M 
24 
M 
36 
Time window 
 
 
±   
4d 
±  
1w 
±  
1w 
±  
2w 
± 
4w 
± 
4w 
± 
6w 
±  
6w 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Randomisation  
 
X 
 
 
 
 
 
 
 
 
Skin thickness  
 
X 
 
 
 
 
 
 
 
 
Length of abutment  
 
 
X 
 
 
 
 
 
 
 
 
Implant surgery  
 
X 
 
 
 
 
 
 
 
 
Time to perform surgery  
 
X 
 
 
 
 
 
 
 
 
Implant stability  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Suture removal  
 
 
X 
 
 
 
 
 
 
 
Wound healing  
 
 
X 
X 
X 
X 
X 
 
 
 
Baha installation  
 
 
 
X  
 
 
 
 
 
 
Use of sound processor2 
 
 
 
 
X 
X 
X 
X 
X 
X 
Change of abutment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Loss of implant  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Holgers index 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Soft tissue 
thickening/overgrowth 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Visible abutment length   
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Aesthetic evaluation 
surgeon  
 
 
 
 
 
X 
 
X 
 
X 
Aesthetic evaluation incl. 
pain question (POSAS) 3 
 
 
 
 
 
X 
 
X 
 
X 
Pain2, 3 
 
 
X 
X 
X 
 
X 
 
 
X 
Numbness 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Use of nicotine2 
X 
 
 
X 
 
X 
 
X 
X 
X 
Health Utility Index2 
X 
 
 
 
 
 
X 
X 
 
X 
Abbreviated Profile of 
Hearing Aid Benefit2 
X 
 
 
 
 
 
X 
X 
 
X 
Extra visits  
 
 
X 
X 
X 
X 
X 
X 
 
 
Concomitant treatment 
 
 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medication 
 
 
X 
X 
X 
X 
X 
X 
 
 
Device deficiency  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
 
 
ADE 
 
 
 
 
 
 
 
 
X 
X 
1 The time between visits will be calculated from visit 1 (time 0) 
2 To be completed by subject on questionnaires  
3  Pain question included in the POSAS scale 

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Table of Contents 
Investigational sites ............................................................................................................... 2 
Clinical investigation management ........................................................................................ 2 
Synopsis................................................................................................................................ 3 
Flow chart ...................................................................................................................... 6 
Abbreviations .......................................................................................................................10 
1 
Introduction ...................................................................................................................11 
1.1 
Background ............................................................................................................11 
1.1.1 
Clinical experience with Baha ..........................................................................11 
1.1.2 
Less invasive surgery ......................................................................................11 
1.1.3 
Abutment design and materials .......................................................................12 
1.1.4 
Cochlear Baha BA400 Abutment ...............................................................12 
1.1.5 
Pre-clinical results on hydroxyapatite-coated Baha abutments ........................13 
1.2 
Rationale ................................................................................................................13 
1.3 
Objectives ..............................................................................................................14 
1.3.1 
Primary clinical objective .................................................................................14 
1.3.2 
Primary economic objective .............................................................................14 
1.3.3 
Secondary objectives ......................................................................................14 
1.3.4 
Tertiary objective .............................................................................................14 
2 
Statement of compliance ..............................................................................................15 
2.1.1 
Ethical requirements for the conduct of the investigation .................................15 
2.1.2 
Regulatory requirements for the conduct of the investigation ..........................15 
2.1.3 
Updates ...........................................................................................................15 
2.1.4 
Quality standards ............................................................................................15 
3 
Medical device(s) used in and after the investigation ....................................................16 
3.1 
Investigational device(s) and comparator(s) ...........................................................16 
3.1.1 
Investigational device(s) ..................................................................................16 
3.1.2 
Comparator .....................................................................................................17 
3.1.3 
Other medical device or medication to be used during the investigation ..........17 
3.1.4 
Treatment after the completion of the investigation .........................................18 
4 
Subjects ........................................................................................................................19 
4.1 
Selection of subjects ..............................................................................................19 
4.1.1 
Inclusion criteria ..............................................................................................19 
4.1.2 
Exclusion criteria .............................................................................................19 
4.1.3 
Number of subjects .........................................................................................19 
4.2 
Subject enrolment and Informed consent ...............................................................19 
4.3 
Randomisation .......................................................................................................20 
4.4 
Discontinuation .......................................................................................................20 
4.5 
Replacement of subjects ........................................................................................20 
4.6 
Insurance ...............................................................................................................20 
5 
Design of the clinical investigation ................................................................................21 
5.1 
Rationale for the design of the clinical investigation................................................21 
5.2 
Variables ................................................................................................................21 
5.2.1 
Primary efficacy variables ...............................................................................21 
5.2.2 
Secondary efficacy variables ...........................................................................21 
5.2.3 
Tertiary efficacy variables ................................................................................22 
5.2.4 
Safety variables ...............................................................................................22 
5.2.5 
Demographics and baseline variables .............................................................22 
5.2.6 
Concomitant medications and treatments ........................................................22 
5.3 
Investigational flow chart ........................................................................................23 
6 
Procedures ...................................................................................................................24 

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6.1 
Skin thickness and length of abutment ...................................................................24 
6.1.1 
BA300 abutment .............................................................................................24 
6.1.2 
BA400 abutment .............................................................................................24 
6.2 
Surgery ..................................................................................................................24 
6.3 
Removal of sutures ................................................................................................25 
6.4 
Baha sound processor installation ..........................................................................25 
6.5 
Change of abutment ...............................................................................................25 
6.6 
Extra visit(s) ...........................................................................................................25 
7 
Assessments ................................................................................................................26 
7.1 
Subject demographics ............................................................................................26 
7.2 
Medical history .......................................................................................................26 
7.3 
Efficay variables .....................................................................................................26 
7.3.1 
Holgers index ..................................................................................................26 
7.3.2 
Soft tissue thickening/overgrowth scale ...........................................................26 
7.3.3 
Direct medical cost ..........................................................................................27 
7.3.4 
Wound healing ................................................................................................27 
7.3.5 
Visible abutment length ...................................................................................27 
7.3.6 
Aesthetic evaluation ........................................................................................27 
7.3.7 
Pain .................................................................................................................28 
7.3.8 
Numbness .......................................................................................................28 
7.3.9 
Health Utilities Index Mark 3 (HUI3) ................................................................28 
7.3.10 
The Abbreviated Profile of Hearing Aid Benefit (APHAB) ................................28 
7.3.11 
Information recorded during surgery ................................................................28 
7.3.12 
Use of sound processor ..................................................................................28 
7.3.13 
Implant Stability Quotient (ISQ) .......................................................................29 
7.3.14 
Smoking habits ................................................................................................29 
7.4 
Safety variables ......................................................................................................29 
7.4.1 
Loss of implant ................................................................................................29 
7.4.2 
Device deficiency reporting .............................................................................29 
7.4.3 
Adverse Event (AE) and Serious Adverse Event (SAE) ...................................29 
7.4.4 
Reporting to ethical committees and regulatory authorities..............................30 
7.5 
Concomitant medication and treatments ................................................................31 
8 
Risk and benefits of the investigational device(s) and the clinical investigation .............32 
8.1 
Anticipated clinical benefits ....................................................................................32 
8.2 
Anticipated adverse device effects .........................................................................32 
8.3 
Residual risks associated with the investigational device .......................................32 
8.4 
Risks associated with participation in the clinical investigation ...............................33 
8.5 
Steps that will be taken to control or mitigate the risks ...........................................33 
8.6 
Risk-to-benefit assessment ....................................................................................33 
9 
Statistical consideration ................................................................................................34 
9.1 
Statistical Design and Hypotheses considerations .................................................34 
9.1.1 
Primary statsitical aims ....................................................................................34 
9.1.2 
Secondary statistical aims ...............................................................................34 
9.2 
Sample size calculation ..........................................................................................34 
9.2.1 
Sample size calculation for the combined endpoint of infection/inflammation, 
overgrowth, pain and numbness ...................................................................................34 
9.2.2 
Sample size calculation for direct medical costs, based on time for surgical 
procedures, wound healing and complications ..............................................................35 
9.3 
Analysis sets – populations ....................................................................................35 
9.4 
General statistical methodology..............................................................................35 
9.5 
Efficacy analysis .....................................................................................................36 
9.5.1 
Primary efficacy analyses ................................................................................36 
9.5.2 
Secondary efficacy analysis ............................................................................36 
9.5.3 
Tertiary efficacy analysis .................................................................................36 
9.6 
Safety analyses ......................................................................................................36 

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9.7 
Analyses of concomitant medications and treatments ............................................36 
9.8 
Demographics and baseline characteristics............................................................36 
9.9 
Interim analysis ......................................................................................................37 
9.10 
Statistical Analysis Plan ......................................................................................37 
10 
Administrative part ........................................................................................................38 
10.1 
Training ..............................................................................................................38 
10.2 
Investigational data .............................................................................................38 
10.2.1 
Case report form .............................................................................................38 
10.2.2 
Source data .....................................................................................................38 
10.2.3 
Data management ...........................................................................................38 
10.3 
Archiving .............................................................................................................38 
10.4 
Device accountability ..........................................................................................38 
10.5 
Quality control .....................................................................................................39 
10.5.1 
Monitoring .......................................................................................................39 
10.5.2 
Audit ................................................................................................................39 
10.6 
Clinical Investigation Plan ...................................................................................39 
10.6.1 
Deviations from Clinical Investigation Plan ......................................................39 
10.7 
Suspension or premature termination .................................................................39 
10.8 
Publication policy ................................................................................................39 
10.9 
Timetable ............................................................................................................40 
10.9.1 
First subject in : Q4 2012 ................................................................................40 
10.9.2 
Last subject last visit: Q2 2016 ........................................................................40 
10.9.3 
Definition of end of investigation ......................................................................40 
11 
Signed agreement – sponsor ...................................... Error! Bookmark not defined..43 
12 
Signed agreement – co-ordinating investigator ............ Error! Bookmark not defined.44 
 

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Abbreviations 
 
 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
APHAB 
Abbreviated Profile of Hearing Aid Benefit 
Baha  
Bone anchored hearing device 
BCI 
Bone Conduction Implants 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form  
HRQL 
Health-Related Quality of Life 
HUI 
Health Utility Index 
ID 
Investigational Device  
ITT 
Intention To Treat 
ISO 
International Organization for Standardization 
ISQ 
Implant Stability Quotient 
MDD 
Medical Device Directive 
MedDRA 
Medical Dictionary for Regulatory Activities 
POSAS 
Patient and Observer Scar Assessment Scale 
PP 
Per Protocol  
PT 
Preferred Term  
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event   
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
USADE 
Unanticipated Serious Adverse Device Effect 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 
Introduction  
 
1.1 Background 
 
1.1.1 
Clinical experience with Baha 
 
Bone conduction implants (BCI) such as the Baha® system  were first clinically described in 1977 by 
Tjellström et al.1, and since then more than 80 000 patients have been treated with this technique. 
 
The Baha system consists of a titanium implant, which is integrated with the bone tissue of the skull 
and is connected to an external sound processor via a skin penetrating abutment. The sound 
processor transforms sound to vibrations that are transmitted via the abutment and titanium implant to 
the skull bone and then to the cochlea. 
 
The surgical procedures that are currently used for Baha surgery make use of a dermatome or scalpel 
techniques (e.g. linear or C-shaped incisions) to remove subcutaneous tissue down to the periosteum, 
thus creating a thin, hair-free skin flap. The rationale for skin thinning is to reduce the mobility of the 
skin surrounding the abutment to minimise the risk for infection or other local skin reactions. 
 
Despite extensive soft tissue reduction, the most common complications associated with Baha 
implants are related to adverse skin reactions around the abutment. The reduction of the skin also 
adds complexity to the surgical procedure that is otherwise a routine type of skin incision. A less 
invasive surgical technique avoiding reducing the thickness of the skin would render a simpler and 
shorter procedure and would be aesthetically appealing to the patients, as permanent hair removal in 
the area around the abutment would not be required. Faster healing and less numbness (sensory 
loss/ paraesthesia) at the implant site may also be expected if the soft tissue thickness is left intact.  
 
 
1.1.2 
Less invasive surgery 
 
Recent published investigations have indicated that good outcomes may be achieved using surgical 
procedures without skin thinning. In a 12 month prospective follow-up study by Hultcrantz2, seven 
patients who underwent surgery without skin thinning using a linear incision technique (test group) 
were compared to seven age–matched patients who underwent standard surgery with skin thinning 
using the dermatome technique (control group). The following results were reported: 
 
 
The mean time required for surgery was 28.1 and 44.6 minutes for the test and control groups, 
respectively (p=0.004). 
 
The wounds of all patients in the test group had healed after 10 days, whereas 71.4% of the 
patients in the control group required a prolonged healing period of up to two months (p = 
0.02) 
 
One patient in the test group showed an adverse tissue reaction compared to three patients in 
the control group 
 
Numbness was reported by one patient in the test group at 12 months compared to six 
patients in the control group 
 
The aesthetic outcome, as judged by the investigator, was reported to be “far better” in the 
test group compared to the control group  
 
In addition Soo et al.3  reported on their experience with Baha surgery without soft tissue reduction or 
skin grafting. Between June 2007 and March 2011, 32 patients had undergone Baha surgery with the 
new technique, 21 adults and 11 children.  Twelve skin reactions were observed. Two fixtures were 
explanted for clinical and social reasons, and implant loss occurred in one child (age 6) with thin soft 

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bone. No implant loss due to periabutment infection or periabutment hyperplasia was observed. The 
authors conclude that this surgical technique appears to have an acceptably low rate of observed skin 
reactions. 
 
 
1.1.3 
Abutment design and materials 
 
While the above investigations show encouraging outcomes and indicate that sufficient soft tissue 
stability may be achieved without reducing subcutaneous tissues, it should be noted that, although 
titanium is known to possess excellent biocompatibility and is widely used as an implant material 
thanks to its unique ability to osseointegrate in bone, it is not known to integrate firmly in dermal 
tissues4. Findings in the literature indicate that soft tissue stability may be improved by the use of 
improved abutment designs5 and/or improved materials. Recent developments in Baha abutment 
design have shown improved clinical outcomes, in terms of a significant reduction in adverse skin 
reactions when used with soft tissue reduction, compared to previous generation abutments19. Ideally, 
the Baha abutment should provide conditions for integration with the surrounding soft tissue, thus 
immobilising the surgical flap, and eliminating/reducing the need for removal of subcutaneous soft 
tissue.  
 
 
1.1.4 
Cochlear Baha BA400 Abutment 
 
In order to remove the need to perform soft tissue reduction during Baha surgery to improve the 
cosmetic outcome and further simplify the Baha surgical procedure a new abutment (Cochlear 
Baha BA400 Abutment) has been developed by Cochlear Bone Anchored Solutions , Mölnlycke, 
Sweden. The new abutment has a design aimed to improve soft tissue adherence to the abutment and 
limit pocket formation, which is believed to be key for maintaining good soft tissue health. The 
abutment has been designed with a concave shape at the lower aspect of the abutment, and the 
titanium surface has been partly coated with a hydroxyapatite layer.  
 
 Cochlear  Baha BIA400  
 
The concave shape is believed to be beneficial in stabilising the soft tissue by increasing the length of 
the soft tissue-to-implant contact and by creating a void space in which a blood clot may form and 
provide space for new soft tissue regeneration as proposed by Rompen et al5.  
Hydroxyapatite is a well-known biomaterial, which finds its application in different types of medical 
implants, such as orthopaedic and dental implants. Pre-clinical and clinical investigations on different 
percutaneous implant devices have shown that hydroxyapatite provides enhanced soft tissue contact 
thus limiting epidermal down growth and pocket formation (providing a barrier against bacterial 
infiltration) and stabilising the soft tissue. 6, 7, 8, 9, 10, 11 
 
 
 

 13 (44) 
 
 
1.1.5 
Pre-clinical results on hydroxyapatite-coated Baha abutments 
 
A pre-clinical investigation has been performed by researchers at the University of Gothenburg 
(Sweden) to evaluate the soft tissue response to experimental Baha abutments with and without a 
hydroxyapatite surface and with and without a pronounced concave shape18. The study included 6 
adult sheep receiving a total of 36 Cochlear Baha BI300 4mm implants with pre-mounted 9mm 
abutments of 4 different types: (A) Cochlear Baha BA300 abutment, (B) BA300 abutment coated 
with hydroxyapatite, (C) concave titanium abutment, and (D) concave titanium abutment coated with 
hydroxyapatite. The implants and abutments were inserted in the skull without performing soft tissue 
reduction. The sites were left to heal for 1, 2 and 4 weeks (2 animals per time point) before samples 
were analysed by descriptive histology and morphometric measurements of pocket depth and 
epidermal downgrowth.  
 
The histological samples showed tight contact between hydroxyapatite-coated abutments and 
surrounding soft tissues with minimal epidermal downgrowth and absence of inflammation, while 
weaker adherence often associated with significant epidermal downgrowth and pocket formation was 
noted for non-coated titanium abutments. The smallest pocket depth and epidermal downgrowth was 
recorded for the hydroxyapatite-coated concave abutment (abutment type D) which had the same 
design as the new BA400 abutment. The mean pocket depth for abutment types A, B, C and D was 
1.38 mm (SD 1.22), 0.42 mm (SD 0.75), 1.51 mm (SD 0.69) and 0.24 (SD 0.39), respectively; the 
difference between C and D was statistically significant (p=0.031). Evaluation of samples with different 
healing times showed stable—and possibly decreasing—pocket depth for hydroxyapatite-coated 
between 2 and 4 weeks of healing, while a trend towards increasing pocket depths was noted for non-
coated titanium abutments. The presence of a blood clot was noted after 1 week of healing within the 
concavity of a number of concave-shaped abutments; such histological pattern was not noted on 
samples with the standard shape. At the later time points, the concavity became filled with soft tissue. 
This observation is in line with data from the dental literature5, and suggests that the concave shape 
may further stabilise the soft tissue by creating a void space where new tissue regeneration can take 
place, resulting in localised thickening and improved stability of the soft tissue. 
 
In conclusion, the results from the pre-clinical investigation showed improved soft tissue adherence 
and significantly reduced pocket depth for hydroxyapatite-coated compared to non-coated abutments 
placed without soft tissue reduction.  
 
 
1.2 Rationale  
 
The Cochlear Baha BA300 Abutment  together with a surgical procedure that includes soft tissue 
reduction was CE marked in April 2010. The new abutment, Cochlear Baha BA400, together with a 
surgical procedure that does not require soft tissue reduction was CE marked in June 2012.  
 
The rationale behind this investigation is to make a ‘head-to-head’  comparison between the BA300 
and BA400 and the associated surgical techniques in order to get information regarding complications 
(inflammation/infection, numbness and pain), aesthetic outcome and utilisation of direct medical cost 
associated with surgery. 
 
 
 
 
 
 
 

 14 (44) 
 
 
1.3 Objectives  
 
1.3.1 
Primary clinical objective 
 
To demonstrate that the minimally invasive surgical procedure in combination with the use of the 
BA400 abutment is associated with a reduction of inflammation/ infection, overgrowth, pain and 
numbness at the site of implantation compared to the traditional surgical procedure in combination 
with the use of the standard Baha abutment (Cochlear Baha BA300 Abutment). 
 
1.3.2 
Primary economic objective 
 
To demonstrate that the new surgical procedure in combination with the use of the BA400 abutment is 
associated with a reduction in direct medical costs, due to shorter surgical procedures, faster wound 
healing and less complications compared to the traditional surgical procedure in combination with the 
use of the standard Baha abutment (Cochlear Baha BA300 Abutment). 
 
 
1.3.3 
Secondary objectives 
 
 
To demonstrate that the new surgical procedure and use of the BA400 in comparison with 
traditional surgical procedure and the use of BA300, is associated with: 
 
 
Less symptoms of inflammation and infection (Holgers index) 
 
Less tissue thickening/overgrowth  
 
Less pain  
 
Less numbness 
 
Faster wound healing  
 
Better aesthetic 
 
Shorter surgical procedures 
 
 
 
 
Safety evaluation (loss of implant, adverse events and device deficiency)  
 
. 
1.3.4 
Tertiary objective 
 
To demonstrate that subjects experience an improved quality of life when receiving a Baha. 

 15 (44) 
 
 
2 
Statement of compliance 
 
2.1.1 
Ethical requirements for the conduct of the investigation  
 
The investigation will be conducted in accordance with the ethical principles as described in the latest 
version of the Declaration of Helsinki adopted by the World Medical Association. 
 
The Clinical Investigation Plan (CIP), the informed consent form and any other written information that 
will be given to subjects will be submitted to the appropriate ethics committee.  
 
 
2.1.2 
Regulatory requirements for the conduct of the investigation  
 
The investigation does not need approval from regulatory authorities within EU  since the 
investigational devices are CE marked for the intended use described in this CIP. 
 
The investigation will be conducted in accordance with applicable local regulations, e.g. data 
protection legislation. 
 
 
2.1.3 
Updates  
 
The appropriate ethics committees shall after initial approval of the investigation receive the following 
information: 
 
 
Status reports and written summary of the investigation as required by the ethics 
committee  
 
Documentation required in order to apply for an extension 
 
Documentation required in order to apply for an amendment to the CIP or the informed 
consent form 
 
Report(s) with new information that may affect the safety of the subjects or the conduct of 
the study  
 
A protocol amendment must be approved by concerned ethics committees and regulatory authorities 
(if applicable). 
 
 
2.1.4 
Quality standards  
 
The staff at the investigational site and the Sponsor shall follow the guidelines provided in the ISO 
standard ‘Clinical investigation of medical devices for human subjects – Good clinical practice (ISO 
14155:2011)’. 
 

 16 (44) 
 
 
 
3 
Medical device(s) used in and after the investigation 
 
3.1 Investigational device(s) and comparator(s)  
 
3.1.1 
Investigational device(s) 
 
3.1.1.1 Description of the investigational device(s)  
 
The investigational devices are CE marked in the EU for the intended use in this CIP. 
The Cochlear Baha BA400 Abutment has been designed with a concave shape at the lower aspect 
of the abutment. The abutment is made of commercially pure titanium and is coated with a 
hydroxyapatite layer on the entire soft tissue-contacting surface of the abutment up to 3 mm below the 
top surface (2 mm below the top surface on 6 mm abutments). The coating is applied by a plasma-
spray technique and has a thickness of approximately 80 m.  
The abutment is available in four different heights (6 mm, 8 mm, 10 mm and 12 mm, measured from 
below the implant flange) to accommodate different skin thicknesses:. 
 
 
The investigational device (Cochlear Baha BA400 Abutment) is available in 4   
different lengths (6 mm, 8 mm, 10 mm and 12 mm). 
 
 
The abutments are intended for patients with conductive or mixed hearing loss or single sided 
sensorineural deafness. Patients should have sufficient bone quality and quantity to support 
successful implant placement. The abutments are classified as MDD Class IIb medical devices and 
are delivered sterile for single use.  
 
The abutments used in the investigation are pre-mounted on Cochlear Baha BI300 4 mm implants. 
Abutments are also available as separate items, to be used in case of abutment change.  
 
The following CE marked products will be used in the investigation: 
 
Product 
Description 
93329 
BIA400 Implant 4mm with Abutment 6mm 
93330 
BIA400 Implant 4mm with Abutment 8mm 
93331 
BIA400 Implant 4mm with Abutment 10mm 
93332 
BIA400 Implant 4mm with Abutment 12mm 
93333 
BA400 Abutment 6mm 
93334 
BA400 Abutment 8mm 
93335 
BA400 Abutment 10mm 
93336 
BA400 Abutment 12mm 
 
The abutment is compatible with the CE marked surgical instruments for the Cochlear Baha BI300 
implant system.  
 

 17 (44) 
 
 
3.1.1.2 Manufacturer of investigational device(s)  
 
Cochlear Bone Anchored Solutions AB, Mölnlycke, Sweden. 
 
 
3.1.2 
Comparator  
  
3.1.2.1 Description of comparator and justification of the choice  
 
The comparator devices are CE marked in the EU for the intended use in this CIP. 
 
Standard titanium Baha abutments (Cochlear Baha BA300 Abutment) will be used as comparator. 
The BA300 abutment is made of commercially pure titanium and is available in two different lengths (6 
mm and 9 mm).  
 
 
 
 
 
The comparator device (Cochlear Baha BA300 Abutment) is available in 2 different lengths (6 mm 
and 9 mm). 
 
 
The abutments are intended for patients with conductive or mixed hearing loss or single sided 
sensorineural deafness. Patients should have sufficient bone quality and quantity to support 
successful implant placement. The abutments are classified as MDD Class IIb medical devices and 
are delivered sterile for single use. 
 
The abutments used in the investigation are pre-mounted on Cochlear Baha BI300 4 mm implants. 
Abutments are also available as separate items, to be used in case of abutment change. 
 
The following products will be used in the investigation: 
 
Product 
Description 
92127 
BIA300 implant 4mm with abutment 6mm 
92346 
BIA300 implant 4mm with abutment 9mm 
92130 
BA300 abutment 6mm 
92131 
BA300 abutment 9mm 
 
 
3.1.2.2 Manufacturer of comparator 
 
Cochlear Bone Anchored Solutions AB, Mölnlycke, Sweden  
 
 
3.1.3 
Other medical device or medication to be used during the investigation 
 
A soft tissue measuring instrument, to be used to facilitate selection of abutment height during surgery, 
is included in the BA400 system. The device will be CE marked in EU as a Class I product before 
commencing this investigation.  
 
 

 18 (44) 
 
 
A drill extender is also included in the BA400 system. The purpose of the drill extender is to improve 
visibility of the site during drilling. The device will be CE marked in EU as a Class I product before 
commencing this investigation.  
 
The sound processor that will be installed on the abutment will be provided by the clinic in accordance 
with local practice. 
 
3.1.4 
Treatment after the completion of the investigation   
 
Subjects will be treated according to standard treatment at the clinic after the investigation. 

 19 (44) 
 
 
4 
Subjects  
 
4.1 Selection of subjects  
 
4.1.1 
Inclusion criteria 
 
A subject will be eligible for inclusion in the investigation if he/she meets all of the criteria below: 
 
Adult patient, i.e. ≥ 18 years of age 
 
Eligible for the Baha system   
 
Signed informed consent 
 
 
4.1.2 
Exclusion criteria   
 
A subject will be excluded from participation in the investigation if he/she meets any of the criteria 
below: 
 
Patient scheduled for simultaneously bilateral implant surgery  
 
Uncontrolled diabetes as judged by the investigator  
 
Condition that could jeopardize osseointegration and/or wound healing, e.g. osteoporosis, 
psoriasis and use of corticosteroids   
 
Unable to follow the cleaning instruction 
 
Unable to follow investigational procedures, e.g. to complete quality of life scales 
 
Participation in another investigation with pharmaceuticals and/or device 
 
Condition that may have an impact on the outcome of the investigation as judged by the 
investigator  
 
 
Suitable implant position for the 4 mm implant not found during surgery due to insufficient bone 
quality and/or bone thickness  
 
 
4.1.3 
Number of subjects  
 
106subjects will be included in the investigation in order to have 100 evaluable subjects. The 
justification for the number of subjects is described in section ‘Statistical considerations’. 
 
 
4.2 Subject enrolment and Informed consent  
 
Before a subject is asked to sign an informed consent form an investigator must explain the following 
to the potential investigational subject : 
 
The rationale, aims and objectives of the investigation 
 
Risks and benefits 
 
Alternative treatments 
 
Extent of the subject’s involvement  
 
That the subject can withdraw his/hers consent at any time  
 
That the confidentiality of patient data will be maintained at all time 
 
The subject must have the possibility to ask any questions. Signed and dated informed consent from 
potential subjects must be obtained before any investigational procedure can be performed. The 

 20 (44) 
 
 
investigator will after informed consent has been obtained, assign a unique enrolment number to the 
subject.  
 
 
4.3 Randomisation  
 
Subjects will be randomised to either: 
 
 
Test group: Minimally invasive surgery and the use of Cochlear Baha BA400 Abutment 
(investigational device). 
 
or  
 
 
Control group: Traditional surgery and the use of  Cochlear Baha BA300 Abutment  
(comparator). 
 
Randomisation will be performed in a proportion 1:1 ratio (test group/control group) at visit 2, i.e. the 
day of surgery, stratified for site with unknown block size. 
 
Randomisation will be based on optimal allocation using a Web-based application.  
 
If a subject discontinues participation in the investigation (see Section ‘Discontinuation’) his/her 
randomisation code/subject number will not be re-used. Discontinued subjects are not allowed to re-
enter into the investigation.  
 
 
4.4 Discontinuation 
 
 
Subjects are free to discontinue their participation in the investigation at any time 
 
Subjects may be discontinued from the investigation at any time at the discretion of the 
investigator 
 
Subjects who themselves discontinue from the investigation should always be asked about the 
reason(s) for the discontinuation and the presence of any adverse events. If possible, the subject 
should always be seen and assessed by an investigator. Any adverse event should be followed up.  
 
 
4.5 Replacement of subjects 
 
If a subject discontinues participation in the investigation, he/she will not be replaced.  
 
 
4.6 Insurance  
 
In case of any damage or injury occurring during the participation in the investigation, the Sponsor has 
contracted an insurance company , Willis, which will cover the liability of the Sponsor, the investigators 
and other persons involved in the investigation. The Sponsor may use a local insurance company, 
where applicable, according to national legislation. 
 
 

 21 (44) 
 
 
 
5 
Design of the clinical investigation  
 
The investigation is designed as an international multicentre, open, randomised, comparative, parallel 
group, prospective clinical investigation. A one year investigation with a two year follow-up. 
 
5.1 Rationale for the design of the clinical investigation 
 
This investigation is designed to evaluate the approved surgical techniques and the two abutments 
whit the standard procedures when it comes to fitting the sound processor and the follow-up visits at 
the clinics remains the same. 
 
The rationale for a one year investigation is that within this time period the initial wound healing has 
occurred, the patients are used to live with the sound processor and that problems with the scar 
(inflammation/infection) normally has occurred. In order to collect long-term data a two year follow-up 
has been added to the initial investigation.   
 
In order to have a fair comparison the patients will be randomised to one of the two treatments. 
 
 
5.2 Variables 
 
5.2.1 
Primary efficacy variables   
  
The first primary endpoint, a combined endpoint of infection/inflammation, overgrowth, pain and 
numbness will be evaluated, as the sum of the following four events: 
1. Holgers Index >=2 any time between 3 weeks to 1 year 
2. Any overgrowth any time between 3 weeks to 1 year 
3. Pain (scar/neuropathic) according to POSAS >=3 any time between 3 weeks to 1 year 
4. Any numbness any time between 3 weeks to 1 year 
 
The second primary endpoint: direct medical cost associated with the surgery (time to perform 
surgery, number of wound dressings sessions and cost to treat complications) will be calculated for 
each subject  using standard cost/unit in each participating country. 
 
5.2.2 
Secondary efficacy variables   
 
The secondary efficacy variables will be evaluated as follows: 
 
 
Infections/inflammations will be evaluated by the Holgers Index 
 
Soft Thickening/overgrowth scale (0-2) 
 
Wound healing will be evaluated by the surgeon/surgical nurse.   
 
Numbness (paraesthesia) – the patients will indicate if they experience numbness and the area 
where they have the problem on a scale from 0-2. 
 
Pain in the scar area and neuropathic pain will be evaluated  by the patient using ‘The Patient and 
Observer Scar Assessment Scale (POSAS)’ (1-10) 
 
Aesthetics will be evaluated by the subject and the surgeon using ‘The Patient and Observer Scar 
Assessment Scale (POSAS)’(two scales): 
- Patient  aesthetic scale (1-10) 
- Observer aesthetic scale (1-10) 
 
Surgery time (min) 
 
 

 22 (44) 
 
 
5.2.3 
Tertiary efficacy variables  
 
Improved quality of life when receiving a Baha will be evaluated by: 
 
 
A generic quality of life scale - Health Utility Index (HUI)  
- HRQL score for overall health 
- Vision score 
- Hearing score 
- Speech score 
- Ambulation/mobility score 
- Dexterity score 
- Self-care score 
- Emotion score 
- Cognition score 
 
 
A disease specific quality of life scale -  Abbreviated Profile of Hearing Aid Benefit (APHAB) 
 
 
Usage of the Baha (sound processor) 
 
Implant stability (ISQ) 
 
Visual abutment length  
 
 
5.2.4 
Safety variables   
 
 
Loss of implant 
 
Adverse Events 
 
Serious Adverse Events 
 
Device deficiency 
 
 
5.2.5 
Demographics and baseline variables 
 
 
Age 
 
Gender 
 
Ethnical background 
 
Medical and surgical history 
 
Current medications and treatments 
 
Type of hearing loss 
 
Skin thickness 
 
Length of abutment 
 
Nicotine use 
 
 
5.2.6 
Concomitant medications and treatments 
 
 
Use of concomitant medications and nicotine 
 
Use of concomitant treatments 
 

 23 (44) 
 
 
 
5.3 Investigational flow chart 
Table 1: Flow chart 
Procedures and timing  
Visit 1 
Baseline 
Visit 2 
Surgery 
 
Visit 
3 
Visit 
4 
Visit  
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit  
10 
Day/Week/Month1 
Before 
day of 
surgery 
D 
0 
D 
10 
W 
3 
W 
6 
W 
12 
W 
24 
M 
12 
M 
24 
M 
36 
Time window 
 
 
±   
4d 
± 1w 
±  
1w 
±  
2w 
± 
4w 
± 
4w 
± 
6w 
±  
6w 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Randomisation (see 4.3.) 
 
X 
 
 
 
 
 
 
 
 
Skin thickness (see 6.1) 
 
X 
 
 
 
 
 
 
 
 
Length of abutment  
(see 6.1) 
 
X 
 
 
 
 
 
 
 
 
 Implant surgery (see 6.2) 
 
X 
 
 
 
 
 
 
 
 
Time to perform surgery  
 
X 
 
 
 
 
 
 
 
 
Implant stability  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Suture removal (see 6.3) 
 
 
X 
 
 
 
 
 
 
 
Wound healing  
 
 
X 
X 
X 
X 
X 
 
 
 
Baha installation (see 6.4) 
 
 
 
X  
 
 
 
 
 
 
Use of sound processor2 
 
 
 
 
X 
X 
X 
X 
X 
X 
Change of abutment 
(see 6.5) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Loss of implant  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Holgers index 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Soft tissue 
thickening/overgrowth 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Visible abutment length   
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Aesthetic evaluation 
surgeon  
 
 
 
 
 
X 
 
X 
 
 
Aesthetic evaluation incl. 
pain question (POSAS) 3 
 
 
 
 
 
X 
 
X 
 
 
Pain2, 3 
 
 
X 
X 
X 
 
X 
 
 
 
Numbness 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Use of nicotine2 
X 
 
 
X 
 
X 
 
X 
X 
X 
Health Utility Index2 
X 
 
 
 
 
 
X 
X 
 
 
Abbreviated Profile of 
Hearing Aid Benefit2 
X 
 
 
 
 
 
X 
X 
 
 
Extra visits (see 6.6) 
 
 
X 
X 
X 
X 
X 
X 
 
 
Concomitant treatment 
 
 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medication 
 
 
X 
X 
X 
X 
X 
X 
 
 
Device deficiency  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
 
 
ADE 
 
 
 
 
 
 
 
 
X 
X 
1 The time between visits will be calculated from visit 1 (time 0) 
2 To be completed by subject on questionnaires  
3  Pain question included in the POSAS scale 

 24 (44) 
 
 
6 
Procedures  
 
6.1 Skin thickness and length of abutment 
 
6.1.1 
BA300 abutment 
The 6 mm pre-mounted abutment on the 4mm implant  is for standard use. The 9mm pre-mounted 
abutment on the 4mm implant is for patients with thicker scalps or if regrowth of subcutaneous tissue 
is anticipated. 
 
6.1.2 
BA400 abutment 
 
The surgeon should measure the tissue thickness before local anaesthesia is 
infiltrated. A hypodermic needle, a clamp and a ruler may be used. Thereafter an 
abutment should be selected depending on the tissue thickness  
 
 
 
Tissue thickness (mm)   
Abutment length (mm) 
≤ 4 
6 
5 
8 
 6 
8 
7 
10 
8 
10 
9 
12 
10 
12 
>10 
12 
 
 
6.2 Surgery 
 
Subjects will be randomised to either: 
 
 
Test group: Minimally invasive surgery and the use of BA400 abutments.  
 
Selection of abutment length and surgery shall be performed in accordance with the 
procedure for FAST (one-stage) surgery described in the Surgery Guide.  
In brief, the surgical procedure consists of making a small straight incision through the skin at 
the planned implant site to access the bone and insert a 4 mm implant with a pre-mounted 
BA400 abutment of adequate length. After placing the implant and abutment, the incision is 
sutured back around the abutment ensuring skin edges are everted and in contact with the 
coated part of the abutment. No removal of soft tissues shall be performed, unless the skin is 
too thick to accommodate a 12 mm abutment, in which case some adipose tissue may be 
removed, as described in the Surgery Guide. After closing the incision, suitable dressing and a 
healing cap shall be used.  
 
or 
  
 
Control group: Standard surgery and the use of BA300 abutments.  
 
Surgery shall be performed in accordance with the procedure for FAST (one-stage) surgery 
described in the Surgery Guide.  
Soft tissue reduction at the selected implant site shall be performed using either a dermatome 
technique or a manual technique (e.g. linear or u-shaped incision). The amount of soft tissue 
removal shall be in accordance with the guidelines provided in the Surgery Guide. A 4 mm 
implant with a pre-mounted BA300 abutment shall be inserted. The skin flap shall be sutured 

 25 (44) 
 
 
back in place ensuring that it sits tight to the bone and periosteum. A biopsy punch may be 
used to create a hole for the abutment through the skin flap. Wound dressing and healing cap 
shall be applied following the recommended procedure in the Surgery Guide.  
 
 
 
6.3 Removal of sutures  
 
The sutures will be removed at visit 3 (i.e. 10 days after surgery). The surgeon/surgical nurse will 
determine if the wound requires further wound dressings, and if so, extra visit(s) will be scheduled, 
until the wound is considered healed.   
 
The subject will receive instruction how to take care of skin around the abutment in accordance with 
local practice. 
 
6.4 Baha sound processor installation 
 
A Baha sound processor will be installed to the implant at visit 4 (i.e. 3 weeks after surgery). If the 
wound is not considered sufficiently healed, as judged by the surgeon/surgical nurse, the installation 
shall be delayed to a scheduled subsequent visit or extra visit, when the site is considered sufficiently 
healed. 
 
 
 
6.5 Change of abutment  
 
If, during the course of the study, the surgeon needs to change the abutment, the subject should 
receive an abutment in accordance with the randomisation, i.e. test device or comparator.  
The type and size of abutment, the reason for the abutment change, and any concomitant treatment 
and/or medication provided to the subject at the time of abutment change should be recorded in the 
case report form (CRF).   
 
If the abutment is changed to a longer or shorter abutment during the investigation, ISQ values shall 
be recorded by resonance frequency analysis according to the procedure described in section 7.3.13 
 
 
6.6 Extra visit(s) 
 
Extra visit(s) may be a scheduled visit to change the wound dressing or to follow-up any 
complications. These visits will be recorded on extra pages in the CRF. The following information will 
be recorded: 
 
 
Date  
 
Reason for extra visit  
 
Staff that conducted the visit (surgeon, surgical nurse or audiologist) 
 
Time to perform the visit   
 
Material used  
 
Subjects will be encouraged to contact the clinic for follow-up if anything out of the ordinary occurs, 
e.g. local reaction, loss of the implant  

 26 (44) 
 
 
7 
Assessments  
 
7.1 Subject demographics 
 
The following demographic data will be recorded at inclusion: 
 
 
Date of birth (month and year) 
 
Gender  
 
Ethnical background  
 
Use of nicotine  
 
 
7.2 Medical history 
 
The following subject characteristics will be recorded at inclusion: 
  
 
Relevant medical and surgical history as judged by the investigator 
 
Current concomitant medication and treatments  
 
Type of hearing loss (conductive or mixed hearing loss or single-sided sensorineural 
deafness) 
 
7.3 Efficay variables 
 
7.3.1 
Holgers index 
 
The Holgers Index12 is designed to capture signs and symptoms of inflammation or infection at the site 
of implantation. The scale should be completed at visit 3-10. 
 
The following scale will be used: 
0 
No irritation. Epidermal debris removed, if present 
1 
Slight redness. Local temporary treatment, if needed 
2 
Red and slightly moist tissue. No granulation formation, local treatment and extra controls as            
indicated* 
3 
Reddish and moist; sometimes granulations tissue, revision surgery is indicated* 
4 
R 
Removal of the abutment / implant necessary due to infection* 
Removal of implant for reasons not related to skin problems* 
 
* Should also be reported on the AE page in the CRF. 
 
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
 
 
 
 
 
 
7.3.2 
Soft tissue thickening/overgrowth scale  
 
In order to capture soft tissue thickening/overgrowth the following scale has been developed for this 
investigation. The scale should be completed at visit 3-10. 
 
The following scale will be used: 
0 
No soft tissue thickening or overgrowth 
1 
Slight soft tissue thickening or overgrowth 
2 
Moderate soft tissue thickening or overgrowth. Local treatment and extra controls as                

 27 (44) 
 
 
indicated* 
3 
Marked/distinct soft tissue thickening or overgrowth. Revision surgery is indicated.* 
 
* Should also be reported on the AE page in the CRF 
 
7.3.3 
Direct medical cost  
 
7.3.3.1 Time to perform surgery 
 
The time to perform surgery will be recorded as “skin to skin” time, i.e. the time from first skin incision 
until finishing suturing the wound. Also the attending staff and type of anaesthesia will be recorded.  
 
 
7.3.3.2 Number of dressings  
 
The total number of wound dressings performed, i.e. number of extra visits, duration of visit, staff that 
conducted the visit, and material used. 
 
 
7.3.3.3 Treatment of complications  
 
All resources used to treat complications will be recorded, e.g. extra visits , type of treatment (e.g. 
local treatment, re-surgery, etc), and concomitant medication.  
 
 
7.3.4 
Wound healing  
 
A surgeon or a surgical nurse will at visit 3-7 determine if the wound is healed or not healed.  
 
 
7.3.5 
Visible abutment length 
 
The visible abutment length (from skin to top of the abutment) will be measured at visit 3-10 using a 
ruler. The ruler must be appropriately cleaned before use, by using Isopropanol (99,7%).  
 
 
 
 
7.3.6 
Aesthetic evaluation  
 
The aesthetic outcome of the surgery will be evaluated by the subject and the surgeon at visit 6 and 8.  
The scar will be evaluated in accordance with the Patient and Observer Scar Assessment Scale 
(POSAS) v 2.013 that consists of two parts, a patient scale and an observer scale: 
 
 
The patient scale contains six items (pain, itching, color, stiffness, thickness and irregularity) 
that should be scored 1-10, with 10 indicating the worst imaginable scar or sensation.  
 
The observer scale also contains six items (vascularity, pigmentation, thickness, relief, 
pliability and surface area) that should be scored 1-10. Besides the 10-step scale, category 
boxes are available to score nominal parameters (e.g. type of color).  
 
Both the patient and the observer should finally score the overall opinion of the scar on the 1-
10 scale.  
 
 
} Visible abutment length 

 28 (44) 
 
 
7.3.7 
Pain  
 
The pain question available in the POSAS scale will be completed by the subjects also at visit 3, 4, 5 
and 7 in addition to visit 6 and 8 when all items will be rated on the POSAS scale.  
 
The subject will rate the following question ‘has the scar been painful the past few weeks’ on the 1-10 
scale were 1= no, not at all and 10=yes, very much. 
 
A second pain question will be added to the POSAS scale ‘have you had any neuropathic pain during 
the past weeks’. The same scale as above applies. Investigational staff will explain the meaning of the 
term  ‘neuropathic pain’ before the patient will complete the questionnaire.  
 
 
7.3.8 
Numbness 
 
Subjects will be asked if they experience any numbness around the abutment at visit 3-10. The 
following scale will be used: 
 
1. No numbness  
2. Numbness within  2 cm from the abutment  
3. Numbness within and beyond 2 cm from the abutment  
 
 
 
7.3.9 
Health Utilities Index Mark 3 (HUI3) 
The Health Utilities Index (HUI®) is a generic preference-based system for measuring comprehensive 
health status and health-related quality of life (HRQL). HUI® provides descriptive evidence on multiple 
dimensions of health status, a score for each dimension of health, and a HRQL score for overall 
health. Health dimensions include vision, hearing, speech, ambulation/mobility, pain, dexterity, self-
care, emotion and cognition. Each dimension has 3-6 levels. The subjects will complete the HUI314, 15 
at visit 1, 7 and 8. 
7.3.10 The Abbreviated Profile of Hearing Aid Benefit (APHAB) 
. 
The Abbreviated Profile of Hearing Aid Benefit (APHAB) 16is a 24-item self-assessment, disability-
based inventory that can be used to document the outcome of a hearing aid fitting, to compare several 
fittings, or to evaluate the same fitting over time. The subjects will complete the APHAB at visit 1, 7 
and 8 
 
 
7.3.11 Information recorded during surgery  
 
The following information should be recorded during surgery: 
 
Type of surgery 
 
Skin thickness (skin thickness should not be measured in the control group since it is not 
in accordance with the surgical procedure when soft tissue reduction is performed) 
 
Length of the abutment  
 
Implant stability 
 
 
 
7.3.12 Use of sound processor  
 
The subjects will be asked at visit 6-10 how many days a week and hours per day they use the sound 
processor. Also the type of sound processor will be registered.  
 
 

 29 (44) 
 
 
 
 
7.3.13 Implant Stability Quotient (ISQ) 
 
ISQ will be measured at surgery as a baseline value and at visit 2-10.  
 
The resonance frequency analysis renders an Implant Stability Quotient (ISQ) value ranging from 1 to 
100. Measurements shall be performed at the abutment level. The highest and lowest ISQ value out of 
two perpendicular measurements obtained at each time point shall be recorded, ISQ High and ISQ 
Low.  
 
The Osstell ISQ instrument and SmartPeg Type 55 (Osstell, Gothenburg, Sweden) shall be used. The 
procedure for obtaining ISQ values is described in the manufacturer’s instruction. 
 
7.3.14 Smoking habits  
 
The subjects will at visits 1, 4, 6, 8, 9 and 10 complete a questionnaire regarding the use of nicotine: 
 
 
Subject response  
 
1 
Does not smoke 
 
2 
Less than 10 cigarettes/day 
Low consumption 
3 
Between 11 and 20 cigarettes/day 
Medium consumption 
4 
Between 21 and 40 cigarettes/day 
High consumption  
5 
More than 40 cigarettes/day  
Very high consumption 
 
In Sweden a large proportion of adults use another form of tobacco, wet snuff. In the Swedish 
questionnaire the subjects will be asked if they use wet snuff and if so, the type of product and the 
quantity used per day.  
 
 
 
7.4 Safety variables  
 
7.4.1 
Loss of implant  
 
The loss of implant is defined as the actual loss of the implant from the site of implantation and will be 
recorded from visit 2 and onwards.  
 
 
7.4.2 
Device deficiency reporting  
 
The definition of a device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance. 
 
A device deficiency should be reported to the sponsor. A device deficiency that could have lead to a 
Serious Adverse Event (SAE) should be reported immediately (see next section). 
 
 
 
7.4.3 
Adverse Event (AE) and Serious Adverse Event (SAE)  
 
Term 
Definition  
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in 
subjects, users or other persons, whether or not related to the 
investigational medical device 
Adverse Device Effect 
(ADE) 
Adverse event related to the use of an investigational medical device 

 30 (44) 
 
 
Serious Adverse Event 
(SAE) 
Adverse event that 
a) led to death 
 
b) led to serious deterioration in the health of the subject, that either 
resulted in 
 
a life-threatening illness or injury 
 
a permanent impairment of a body structure or a body 
function 
 
in-patient or prolonged hospitalization 
 
medical or surgical intervention to prevent life-threatening 
illness or injury or permanent impairment 
 
to a body structure or a body function 
 
c) led to foetal distress, foetal death or a congenital abnormality or birth 
defect 
 
Note - Planned hospitalization for a pre-existing condition, or a 
procedure required by the CIP, without serious deterioration in health, is 
not considered a serious adverse event.  
Serious Adverse Device 
Effect (SADE) 
 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event 
Unanticipated Serious 
Adverse Device Effect 
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 
 
 
7.4.3.1 Handling and reporting of AEs and ADEs 
 
Subjects will be carefully monitored during the investigation for possible adverse events and 
appropriate treatment of the subject will be initiated.  
 
Any adverse events observed will be fully investigated by the investigator and documented in the case 
report form (CRF) including assessment of severity (mild, moderate or severe) and relationship to the 
medical device.  
 
At visit 9 and 10 (week 101 and 156) only ADEs needs to be reported. 
 
 
7.4.3.2 Handling and reporting of SAEs and device deficiency that could have lead to a 
SAE 
 
An investigator should report within 24 hours, after being aware of the event, an SAE or a device 
deficiency that could have lead to a SAE. The report should be faxed or sent as a mail attachment to 
Cochlear Bone Anchored Solutions AB. Contact information is available on the SAE form.   
 
 
 
7.4.4 
Reporting to ethical committees and regulatory authorities    
 
SAEs/SADEs/USADEs and device deficiencies that could have led to a SAE should be reported to 
ethics committees/institutional review board  in accordance with local requirements. 
 
 

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7.5 Concomitant medication and treatments 
  
All medications and treatments given, whether or not to treat AEs/ADEs, must be recorded in the 
appropriate section of the case report form. 
 

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8 
Risk and benefits of the investigational device(s) and the 
clinical investigation 
 
8.1 Anticipated clinical benefits 
 
The Cochlear Baha BA400 Abutment has been designed to remove the need to perform soft tissue 
reduction, to reduce skin complications and to improve the cosmetic outcome of the surgery. The 
surgical procedure will also be simplified.  
 
 
8.2  Anticipated adverse device effects 
 
The adjustment in the design of the new abutment is minimal from a risk perspective. Nevertheless the 
following risk with the new abutment BA400 in comparison with the current abutments BA300, has 
been hypothesised: 
 
 
Trauma  
A longer abutment (BA400: 10 mm and 12 mm abutments) could increase the risk for trauma 
in comparison with shorter abutments (BA300 6 mm/9 mm and Baha snap coupling 8.5 mm).  
 
In order to evaluate if longer abutments increase the risk of implant failure a comparison has 
been made between currently available abutments when it comes to reported implant failures 
in the Cochlear Complaint Management System (CREM) in relation to with the number of sold 
products.  
 
The conclusion of the events reported in CREM is that there is no  indication of  an increased 
risk of implant failures with the 9 mm abutment compared to the 6 mm abutment  
Product 
Description 
Number of sold 
products  
Number of 
implant failures  
92127 BIA300 
Implant 4 mm with abutment 6 mm 
11 600 
21 
92346 BIA300 
Implant 4 mm with abutment 9 mm 
1 800 
4 
 
A similar conclusion was drawn based on the literature search of Baha literature. Of the 55 
articles selected for the clinical evaluation four (4) articles covered the use of the 8.5 mm long 
abutments. No implant failures were reported in these studies. 
In conclusion, there exist no anticipated additional adverse device effect in comparison with 
the current abutment (BA300). 
 
 
8.3 Residual risks associated with the investigational device 
 
Clinical outcomes related to the use of Baha implants and abutments have been frequently reported in 
the scientific literature during the last decades. A  literature review17 was performed in June 2012 in 
order to assess the current status of Baha implants and surgical products in terms of safety and 
efficacy. Fifty-five (55) scientific articles met the predefined review criteria. Only one (1) randomised 
controlled prospective study and one (1) non-randomised prospective study were encountered; the 
remaining studies were retrospective studies or case reports. One systematic literature review was 
also included. Ten (10) studies included only paediatric patients, while the remaining studies included 

 33 (44) 
 
 
both paediatric and adult patients or adults only. Nineteen (19) of the studies included 100 or more 
patients.  
 
Overall good outcomes, with acceptable implant survival rates and low incidence of significant adverse 
reactions, are reported. However, as with any surgical procedure, the use of Baha implants and 
surgical procedures is not free from complications, which is also reflected in the literature. Reported 
complications with Baha implants and surgical products are summarised at continuation. 
 
Implant loss is a known complication with Baha implants, and can occur at any time point following 
implantation. Known reasons for implant loss include: primary failure of osseointegration, loss of 
osseointegration, trauma, infection leading to implant loss. The literature reports of cumulative implant 
survival rates in the range 73 to 100%, with the majority of authors reporting survival rates of 90% or 
higher. 
 
Local skin reactions around the Baha abutment, ranging from slight redness to infected tissue, are the 
most common complications with Baha implants. Reports suggest that as many as 30% of the patients 
experience some kind of skin reaction at some point in time. However, the vast majority of skin 
complications are regarded as minor. Holgers grades of 0-1 are reported in 90-95% of observations, 
with adverse reactions (grade 2-4) only being reported in a few percent of observations 
 
Excessive skin thickening or skin overgrowing the abutment is another relatively common soft tissue 
complication. The reported rate of skin thickening/overgrowth ranges between 0 and 22%. In cases 
where skin thickening recurs following localised treatment and skin revision surgery. 
 
Incomplete or complete flap breakdown is another known complication with Baha implantation; this 
complication is generally not regarded as major.  
 
Persistent pain at the implant site requiring removal of the implant has been reported by some author s 
and numbness in the area around the implant site has been reported in one study 
 
8.4  Risks associated with participation in the clinical investigation 
 
The test abutment, the control abutment and associated surgical procedures are CE marked and the 
procedures in this CIP are in accordance with the intended use. 
 
 
8.5 Steps that will be taken to control or mitigate the risks 
 
The surgical procedures associated with BA300 and BA400 are described in the Surgery Guides.  
 
8.6 Risk-to-benefit assessment 
 
After thorough analysis no foreseeable additional risks can be ascribed to the new abutment. 
Therefore the risks/adverse events are minimal and acceptable when weighed against the benefits of 
the intended performance of the investigational device/ comparator.  

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9 
Statistical consideration  
 
9.1 Statistical Design and Hypotheses considerations 
 
9.1.1 
Primary statsitical aims  
 
This study is designed as a superiority study with two primary statistical aims 
 
1.  To demonstrate that the combined endpoint of infection/inflammation, overgrowth, pain and 
numbness will be significantly lower in the group with the minimally invasive  surgical 
procedure in combination with the use of the BA400 abutment compared to the traditional 
surgical procedure  procedure and abutment BA300. 
 
2. To demonstrate that the minimally invasive  surgical procedure in combination with the use of 
the BA400 abutment is associated with a significant reduction in direct medical costs, due to 
shorter surgical procedures, faster wound healing and less complications compared to the 
traditional surgical procedure in combination with the use of the standard BA300 abutment. 
 
 
 
9.1.2 
Secondary statistical aims  
 
The secondary statistical aims are to show that the minimally invasive  surgical procedure in 
combination with the use of the BA400 abutment is associated with a significant: 
 
 
reduction in infections/inflammations evaluated by Holgers Index 
 
reduction in soft Thickening/overgrowth scale 
 
reduction in time for wound healing will be evaluated as number of dressings 
 
reduction in numbness 
 
reduction in pain in the scar area and neuropathic pain 
 
reduction in surgery time 
improvement in the aesthetics 
 
 
9.2 
Sample size calculation  
 
Sample size calculations are performed for both primary analyses. The significance level of 0.05 will 
be split between the two primary analyses: combined endpoint 0.0499 and direct medical cost 0.0001.  
 
 
9.2.1 
Sample size calculation for the combined endpoint of infection/inflammation, overgrowth, 
pain and numbness 
 
For a definition of first primary endpoint, see section 5.2.1. It is estimated that the distribution of the 
number of events regarding infection/inflammation, overgrowth, pain and numbness with the traditional 
surgical procedure and BA300 abutment is as follows; 60% no events, 18% one event, 12% two 
events, 7% three events and 3% four events. In order to achieve a power of 80% with the Mantel-
Haenszel two-sided chi-square test at significance level of 0.0499 when the distribution of the number 
of events with the new surgical procedure and new abutment BA400 is as follows;81% no events, 13% 
one event, 5% two events, 1% three events and 0% four events we need 50 statistical evaluable 
subjects in each group. The sample size calculation is based on 10000 simulated studies.  
 

 35 (44) 
 
 
9.2.2 
Sample size calculation for direct medical costs, based on time for surgical procedures, 
wound healing and complications  
 
For a definition of the second primary endpoint see section 5.2.1. The power that is achieved if  the 
previously needed 50 statistical subjects in each group are used for the economic evaluation is 
calculated as follows, From a 12 months prospective follow-up by Hultcrantz2 the mean time required 
for surgery was 44.57 (SD 7.41) minutes with skin reduction and 28.14 (SD 3.67) minutes without skin 
reduction. If a normal distribution of the costs time required for surgery,15% infections/inflammations, 
15% extra dressings with skin reduction, 9% infections/inflammations and 10% extra dressings without 
skin reduction, w a power of more than 99% with the two-sided Mann-Whitney U-test at a significance 
level 0.0001 would be achieved. The sample size calculation is based on 10000 simulated studies. 
 
In order to compensate for a drop-out rate of 5% we need to randomize 53 subjects to each group 
 
 
 
9.3 Analysis sets – populations 
 
The Intention to Treat population (ITT) consists of all randomised patients with at least one follow-up 
measurement. 
 
The per protocol population (PP) will include subjects that have completed the investigation according 
to the protocol. Subjects that were incorrectly randomised or were considered major protocol violators 
should be removed from the PP population. 
 
The safety population consists of all surgical treated patients, grouped after surgical procedure. 
 
The definition of the analyse sets (ITT, PP and Safety) will be taken at the clean file meeting before 
the database lock.  
 
9.4 
General statistical methodology 
 
For comparison between the two study groups the Mantel-Haenszel chi-square test will be used for 
ordered categorical variables, the Mann-Whitney U-test for continuous variables, Fisher’s exact test for 
dichotomous variables and the Chi-square test for non-ordered categorical variables. 
 
The distribution of continuous variables will be given as n, mean, SD, Median, Min and Max and the 
distribution of dichotomous and categorical variables will be given as number and percentages. 
 
The main analyses will be performed on the ITT population and complementary analyses will be 
performed  on the  PP population. 
 
The main analyses will be performed unadjusted. If significant statistical differences in demographics 
and baseline variables are found, complementary analyses will be performed adjusted for these 
variables. 
 
The main analysis will be after 12 months of follow-up and repeated after 3 years.  
All statistical tests will be two-sided.  
 
 
 
 
 
 

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9.5 Efficacy analysis 
 
9.5.1 
Primary efficacy analyses 
 
9.5.1.1 First primary analysis: combined endpoint of infection/inflammation, overgrowth, 
pain and numbness 
 
The primary analysis of the number of events regarding infection/inflammation, overgrowth, pain and 
numbness (see definition section 5.2.1) between the two study groups will be analysed with the 
Mantel-Haenszel two-sided chi-square test at a significance level of 0.0499 on the ITT population 
between 3 weeks and 1 year. 
 
9.5.1.2 Secondary primary analyses: direct medical costs, based on time for surgical 
procedures, wound healing and complications  
 
The primary analysis of direct medical costs, based on time for surgical procedures, wound healing 
and complications (see definition section 5.2.1) between the two study groups will be analysed with 
two-sided Mann-Whitney U-test at significance level 0.0001 on the ITT population up to one year of 
follow-up.  
 
 
9.5.2 
Secondary efficacy analysis 
 
All secondary variables given in section 5.2.2 will be analysed and described with the methods given 
in section 9.4 General statistical methodology. All significance tests will be two-sided and conducted at 
the 5% significance level. 
 
 
9.5.3 
Tertiary efficacy analysis 
 
All tertiary variables given in section 5.2.3 will be analysed and described with the methods given in 
section 9.4 General statistical methodology. All significance tests will be two-sided and conducted at 
the 5% significance level. 
 
 
9.6 Safety analyses 
 
The loss of implants will be analysed with the Log-rank test between the two groups and illustrated 
with Kaplan-Meier survival curves. 
 
Adverse Events and Serious Adverse Events will be coded with the MedDRA dictionary and tabulated 
by PT-code and SOC-code and treatment. 
 
9.7 Analyses of concomitant medications and treatments 
 
Concomitant medications will be coded and tabulated by treatment. 
 
 
9.8 Demographics and baseline characteristics. 
 
Demographics and baseline characteristics are tabulated and analysed by treatment group according 
to the general methodology given in section 9.4. 
 

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9.9 Interim analysis  
 
No interims analysis planned. In addition to the main analysis at one year, only a follow-up analysis 
after 3 years is planned. 
 
9.10 Statistical Analysis Plan  
 
A statistical analysis plan (SAP) with detailed statistical analyses specified for all variables and time 
points will be written and signed before the database lock. 
 
  

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10 
Administrative part  
 
10.1 Training  
 
The Sponsor will organise an initiation visit during which the CIP, investigational procedures including 
the informed consent process, case report form completion and any other matters relating to running 
the investigation at the site should be discussed and queries clarified. 
 
 
The principal investigator will ensure that appropriate training relevant to the investigation is given to 
the medical, nursing and other staff involved at the clinic and that new information of relevance to the 
performance of this investigation is forwarded to the staff involved. 
 
 
10.2 Investigational data  
 
10.2.1 Case report form  
 
A paper document for each subject on which information that will be reported to the sponsor is 
recorded. Specific instructions how to complete the CRF will be provided to the investigator and other 
site staff. Completed CRFs will be reviewed and signed by an investigator.   
 
 
10.2.2 Source data  
 
Defined as all the  information in original records, certified copies of original records of clinical findings, 
observations, or other activities in a clinical investigation, necessary for the reconstruction and 
evaluation of the clinical investigation. 
 
The CRF could be source data and before the initiation of the investigation the principal investigators 
should together with the monitor complete the template ‘Origin of source data’ stipulating where 
source data should be recorded at the investigational site. 
 
 
10.2.3 Data management 
 
A data management plan will be written that describes the overall data handling process including 
data validation, clarification of data and the clean file process. 
 
All outstanding questions regarding data should be taken during the clean file meeting. After declaring 
clean file the data will be locked.  
 
 
10.3 Archiving  
 
The sponsor and principal investigator shall maintain the investigation documents as required by the 
applicable regulatory requirements.  
 
 
10.4 Device accountability  
 
Not applicable since the products are CE marked. 

 39 (44) 
 
 
 
10.5 Quality control  
 
10.5.1 Monitoring  
 
The sponsor will appoint a monitor that will visit sites during the investigation. The monitor will be 
appropriately trained and informed about the nature of the investigation, ISO 14155:2011 and 
applicable regulatory requirements. 
 
The monitor will verify the informed consent of participating subject, that the investigational team is 
adhering to the protocol and that data are accurately recorded in the CRF. 
 
The monitor must have direct access to source data.  
 
 
 
10.5.2 Audit  
 
 Audits of the clinical investigation may be conducted by the sponsor or third party designated by the 
sponsor to evaluate compliance with the CIP, written procedures, ISO-14155:2011 and applicable 
regulatory requirements.  
 
 
10.6 Clinical Investigation Plan  
 
10.6.1 Deviations from Clinical Investigation Plan 
 
Any deviation from the CIP will be recorded together with an explanation of the deviation. Deviations 
will be reported to the sponsor, who is responsible for analysing them and assessing their significance. 
The appropriate ethics committee/institutional review board and regulatory authorities will be informed 
of any significant protocol deviations. 
 
10.7 Suspension or premature termination 
  
The sponsor may suspend or prematurely terminate either an individual investigation site or the entire 
clinical investigation for significant and documented reasons. A principal investigator may suspend or 
prematurely terminate participation in the clinical investigation at the investigation site for which he/she 
is responsible.  
 
10.8 Publication policy 
 
The result of this study will be published. Authors of the primary publication based on this study must 
fulfil the criteria defined by the International Committee of Medical Journal Editors (ICMJE). 
 
The primary publication must be published before any secondary publications are submitted for 
publication.  
 
 
 
 

 40 (44) 
 
 
10.9 Timetable  
 
10.9.1 First subject in : Q4 2013 
 
10.9.2 Last subject last visit: Q1 2017 
  
10.9.3 Definition of end of investigation 
 
End of investigation is defined as ‘last subject last visit. 

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