An Investigation on Function and Performance of a New Microprocessor-controlled Prosthetic Knee
Phase: NA
Conditions: Prosthesis User, Amputation
Sponsor: Össur Iceland ehf

NTC number: NCT05523349
Protocol Date: 29/JUN/2022
 

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Table of Contents 
1 
How to Refer to This Document ............................................................. 5 
2 
Summary .................................................................................................. 6 
3 
Changes from Previous Revision .......................................................... 9 
3.1 
Changes for Revision 1.00 ......................................................................................... 9 
4 
Abbreviations ........................................................................................ 10 
5 
Investigational Device ........................................................................... 11 
6 
Justification for the Design of the Clinical Investigation ................... 14 
7 
Objectives and Hypotheses .................................................................. 16 
8 
Design of the Clinical Investigation ..................................................... 21 
8.1 
General .................................................................................................................... 21 
8.2 
Investigational Device(s) and Comparator(s) ........................................................... 22 
8.3 
Subjects ................................................................................................................... 23 
8.4 
Procedures............................................................................................................... 25 
i)
Recruitment ............................................................................................................................. 25 
ii)
Test procedure......................................................................................................................... 25 
iii)
Measurements and data collection .......................................................................................... 25 
8.5 
Compensation .......................................................................................................... 26 
iv)
Subject ..................................................................................................................................... 26 
8.6 
Responsibilities ........................................................................................................ 26 
8.7 
Study monitoring and Oversight ............................................................................... 27 
9 
Investigational Device Accountability ................................................. 27 
10 
Statistical Considerations .................................................................... 28 
10.1 
Statistical design and procedures ............................................................................ 28 
10.2 
Sample size calculation ........................................................................................... 28 
10.3 
Additional statistical matters..................................................................................... 29 
11 
Amendments and Deviations from the Protocol (CIP) ........................ 29 
11.1 
Amendments ............................................................................................................ 29 
11.2 
Deviations ................................................................................................................ 29 
12 
Statement of Compliance ..................................................................... 30 
13 
Ethical Considerations ......................................................................... 30 
13.1 
Anticipated clinical benefits ...................................................................................... 30 
13.2 
Device related risk ................................................................................................... 30 
13.3 
Risk of Study (To Patient) ........................................................................................ 32 
13.4 
Risk Mitigation .......................................................................................................... 32 
13.5 
Risk-to-Benefit Rationale ......................................................................................... 32 
13.6 
IRB/REB/REC Review and Communications ........................................................... 32 
13.7 
Vulnerable populations ............................................................................................ 32 
13.8 
Informed Consent .................................................................................................... 33 
13.9 
Participant confidentiality – Data management ........................................................ 33 
14 
Evaluation of Adverse Events and Device Deficiencies ..................... 35 

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14.1 
Definitions of adverse events, effects and deficiencies ............................................ 35 
14.2 
Reporting procedures .............................................................................................. 35 
14.3 
Suspension or premature termination of the clinical investigation............................ 36 
15 
Publication Policy ................................................................................. 36 
16 
References ............................................................................................. 37 
17 
Tables 
Table 1 Summary of procedures and visits ......................................................................................................... 7 
Table 2 Identification and Description of the Investigational Device .............................................................. 11 
Table 3 Technical and functional features ......................................................................................................... 14 
Table 4 Claims/MNBA items to be evaluated ..................................................................................................... 17 
Table 5 Phase I Endpoints, test methods and hypotheses .............................................................................. 18 
Table 6 Phase II – Endpoints, test methods and hypotheses .......................................................................... 20 
Table 7 Inclusion/Exclusion criteria ................................................................................................................... 24 
Table 8 Visit schedule and procedures .............................................................................................................. 25 

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How to Refer to This Document
[0]
CIP2022022514,

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 Changes from Previous Revision 
 Changes for Revision 1.00 
Initial release. 
 

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Abbreviations
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ASADE 
Anticipated Serious Adverse Device Effect 
BL 
Baseline 
CI 
Co-Investigator 
COI 
Coordinating Investigator 
CIB 
Clinical Investigator´s Brochure 
CIP 
Clinical Investigation Plan 
CIR 
Clinical Investigation Report 
CRF 
Case Report Form 
DD 
Device Deficiency 
EDS 
Electronic Data capture System 
FU 
Follow-Up 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
IDMF 
Investigational Device Management Form 
IFU 
Instructions For Use 
IRB 
Independent/Institutional Review Board 
LCI 
Local Co-Investigator 
LPI 
Local Principal Investigator 
LRA 
Local Research Assistant 
PI 
Principle Investigator 
PIS 
Participant Information Sheet 
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Event 
SCI 
Sponsor Co-investigator 
SOTA 
State-Of-The-Art 
SRA 
Sponsor Research Assistant 
UE 
Use Error 
UADE 
Unanticipated Adverse Device Effect 

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Microprocessor Controlled Knees (MPK) have become the standard of care for trans-femoral amputees of medium 
to high activity levels (K3-K4). While the functional principles of the different knee joints remain the same, 
differences in the mechanical design can be found.  
The Rheo Knee 4/Navii is a microprocessor-controlled prosthetic knee and employs sensory information, to 
automatically adapt knee damping values to match the amputee’s gait requirements, accounting for variations in 
forward walking speed, walking terrain, user gait styles and body size. The Rheo Knee 4/Navii technology 
generates resistances with a microprocessor-controlled, magnetorheological fluid, which enables continuous 
variation of knee joint resistances in both movement directions. The amount of current determines the viscosity of 
the fluid. Therefore, an adaptable friction moment is generated for both flexion and extension movements at the 
same time. In this study there are two types of comparator devices, hydraulic MPKs and previous version of the 
Rheo knee 4/Navii.  
 
Hydraulic MPKs consist of an integrated microprocessor-controlled linear hydraulic system in combination with a 
control algorithm. They generate knee joint resistances hydraulically with microprocessor-controlled, motorized 
valves. This enables continuous variations in the hydraulic resistance to be set for both movement directions. The 
magnetorheological fluid creates shear forces in comparison to an increase of pressure in a hydraulic system. The 
increased system pressure can lead to higher temperatures and risk of leakage. 
 
The previous version of the Rheo knee/Navii (RK III/RK XC) features the same intended use, same clinical 
purpose, same user population, same placement below the socket, uses a battery powered system and is 
controlled through a software application that can be user configured through a separate computer interface/mobile 
device. The Rheo Knee 4/Navii is an enhancement of the previous version, functional features and indication are 
equivalent to previous version and the same critical functions apply. Features that have been added include a 
mechanical stance locking feature that allows the user to manually lock the knee in 3 different positions in stance 
and the device will be waterproof. The Rheo Knee 4/Navii also includes functions that were only included in the 
Rheo Knee XC configuration of the previous version; automatic cycling and running detection and a stair ascent 
mode.  
Results of a pilot stage exploratory clinical investigation including 25 subjects indicate that the investigational 
device had similar or better performance compared to previous versions of the Rheo knee regarding satisfaction 
on descending activities. This investigation is designed primarily to confirm these indications and that the 
performance of the investigational device regarding descending activities is comparable/no worse than hydraulic 
MPKs.   
Considering previous experience with clinical investigations in prosthetics it was concluded to conduct a non-
randomized prospective repeated measures (ABA) design, comparing subjects’ current MPK at baseline and 3-
week follow-up vs. the investigational device at 3-week follow-up. See Figure 2 Study design and instruments 
below; 
Background information
Baseline measurements
PEQ, ABC, PLUS M, 
AMPro, L-test, 6MWT
(Prescribed device)
Fitting & 
Training on the 
Navii
Visit 1 
3 weeks
adaptation
Visit 2
Measurements 
PEQ, ABC, PLUS M, 
AMPro, L-test, 6MWT,
(Investigational device)
Fitting back to 
prescribed 
device
3 weeks
Back on 
prescribed
Visit 3
Measurements 
PEQ, ABC, PLUS M, 
AMPro, L-test, 
6MWT, qualitative 
interview
(prescribed device)
End of 
study
  
Figure 2 Study design and instruments 
Repeated measures analysis has the advantage of increased power compared to group allocations and reduction 
in error variance associated with individual difference, as each subject acts as its own control. This is important for 
studying amputees as the group is a small proportion of the total population, and with specific inclusion/exclusion 
criteria the total eligible population becomes very small, making it difficult to find and recruit subjects to attain an 

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acceptable level of power. This limited population pool often results in a slightly heterogeneous sample, as the 
amputees available are few and far between, in every sense. Furthermore, no single amputation procedure and 
therefore amputated stump is exactly the same, making the experience of each amputee unique. The within-
subject design significantly reduces the individual differences when comparing the two conditions. 
Once on the market the investigational device will be intended for Unilateral hip-disarticulation or hemipelvectomy 
amputation and Bilateral amputations that combine unilateral amputation on one side with transfemoral level 
amputation or any amputation below that level on the contralateral side. But these will not be included in this 
investigation as the device has not been fully validated in those populations and, to reduce the variability of the 
sample. 
The drawback of the design is the potential of “carryover effects”, i.e. experience from one condition can affect 
outcome or performance in the other condition, creating a confounding extraneous variable that varies with the 
independent variable. Such effects are: practice, positive carryover effect to the latter condition; and fatigue, 
negative carryover effect to the latter condition.  
Along with evaluating the performance aspects listed in Table 4 in Ch. 7, the clinical investigation is designed to 
evaluate whether the investigational device is suitable for the purposes and the population for which it is intended 
(excluding unilateral hemi-pelvectomy and hip disarticulation and bilateral prosthesis users). It is designed in such 
a way as to ensure that the results obtained have clinical relevance and scientific validity and address the clinical 
investigation objectives. 
The study design includes a qualitative interview at the end of the last follow up period. The interview is meant to 
gather additional information on the experiences of the subjects in general as well as on the investigational device 
and, the comparison with their prescribed device regarding specific aspects e.g. safety and security.   
Several studies have provided evidence for the clinical performance of previous versions of the Rheo Knee, which 
is equivalent to the investigational device and has the same function and intended use, those are detailed in the 
Literature review device report [1]. 
For full details of existing clinical data and pre-clinical data on the investigational device see Investigators Brochure 
[2]. 
 Objectives and Hypotheses 
The primary objective of this study is to evaluate the efficacy of the investigational device compared to other 
passive MPKs (Rheo Knee 4, C-leg 4, Genium, X3, Plié 3, Orion 3, Quattro, Allux) regarding satisfaction in 
descending activities for moderate to high active prosthesis users within the intended population for the 
investigational device. 
Additionally, to evaluate the balance confidence, perception of safety and comfort in standing with the 
investigational device compared to other passive MPKs (Rheo Knee 4, C-leg 4, Genium, X3, Plié 3, Orion 3, 
Quattro, Allux). 
For justification of study design please refer to Chapter  above.  
In phase I the performance in descending activities will be compared to any other passive MPK and in phase II 
there will be a subgroup analysis comparing to hydraulic MPKs and Rheo Knee 3, specifically.    
The following clinical claims/MNBA items as defined in the Clinical evaluation plan [3] are to be evaluated: 

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2B2 
Users satisfaction on 
functioning on the  Rheo 
knee 4/Navii in stair descent 
is improved compared to 
Rheo Knee 3 
Self report: 
Modified PEQ 
ampulation subscale 
(item 13D) 
Please rate how you felt 
about being able to walk 
down stairs when using 
your prosthesis/the test 
prosthesis? 
1=cannot, 10=No 
problem 
Rating (1-10) 
Improved rating 
compared to 
prescribed 
magentorheologic 
MPK 
(89% 𝐻𝐷𝐼௟௢௪≥0 
𝑝𝑑> 97,0% 
𝑅𝑂𝑃𝐸< 2,5% ) 
 
 
 Design of the Clinical Investigation 
 General 
The test will be a non-randomized single group open label prospective repeated measures (ABA) design.  
Amputees are a small proportion of the general population. The population group specified in the 
inclusion/exclusion criteria is a further subsample of amputees. For practical reasons, i.e. to achieve statistical 
power, it is therefore more feasible to use within-subject comparison rather than creating study arms to compare. 
Furthermore, as mobile amputees generally have and use a prosthetic device for their daily activities, within-
comparison is feasible comparing to the subject’s previous device. 
All investigational activities will be conducted at prosthetic out-patient clinics.  
As stated above the primary endpoint is Satisfaction on descending stairs, see Table 5, and the secondary 
endpoints are satisfaction on descending ramps, balance confidence and standing comfort in that respective order 
of significance. In addition, there are two exploratory endpoints on mobility and balance during ambulation. See 
previous chapter on objectives and hypothesis and Table 5 for rationale. 
Drop-outs and withdrawals may be replaced if deemed necessary to fulfil the methodological standards of the 
study. 
Instruments for data collection will include the following:  
The Six Minute Walk test (6MWT) is simply a record of the distance traveled by a given patient at his or her self-
selected walking speed over a period of six minutes. All that is required is a stopwatch and a walking corridor or 
track of known distance16,17.  
The Amputee mobility predictor (AMPro) is a 20-item scale that was originally developed to provide a more 
objective approach to the assignment of Medicare K-levels. The scale includes tasks intended to assess sitting 
balance, transfers, standing balance, gait, and obstacle negotiation and takes around 15 minutes to administer17.  
The Prosthesis Evaluation Questionnaire (PEQ) measures prosthetic-related quality of life. It consists of 82 items 
grouped into nine subscales. In addition, there are individual questions not contained in the subscales regarding 
satisfaction, pain, transfers, prosthetic care, self-efficacy, and importance18. This study will include a set of 
subscales from the PEQ, including specific questions on descending activities. 
L-test of functional mobility is a modified version of the Timed up and go test (TUG) developed for more active 
lower limb amputees. The patient begins the test seated in a chair, ideally positioned in an exam room and facing 
the entrance to the hallway. The patient rises from the chair, walks three meters into the hallway, turns 90 degrees 
and then walks an additional seven meters down the hallway. Upon completing seven meters, he turns 180 

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degrees, returns down the hallway, turns 90 degrees to face the exam room, and returns the three meters to his 
chair, where he retakes his seat19 
The Plus-M is a self-report instrument for measuring mobility of adults (age 18+) with lower limb amputation who 
have experience of using a prosthesis. PLUS-M measures prosthetis users’ mobility (i.e., their ability to move 
intentionally and independently from one place to another). The questions assess respondents’ perceived ability 
to carry out specific activities that require use of both limbs. PLUS-M questions cover movements that range from 
basic ambulation such as walking a short distance indoors to more complex outdoor activities such as hiking for 
long distances20,21. 
Usability questionnaire: In-house generated questionnaire on specific features in the investigational device e.g. 
water proof, interaction with the app, running and cycling mode.  
Video 
Data logging by Össur Logic 
Qualitative interview  
 
See Error! Reference source not found. Appendix I for details of all instruments to be used and Error! Reference 
source not found. Appendix II for qualitative interview script.  
 
See chapter 10.2 Sample size calculation and Table 5 for analysis of variables. 
Equipment required for each subject: 
 
Investigational device (see section  Investigational device) 
 
Other components as applicable (prosthetic feet, adapters) 
 
Tools for fitting 
 
Detailed protocol 
 
Case report forms (CRFs) in Smart-Trial – Tablet/computer OR Printed out Case report forms (CRFs 
including instruments listed above) 
 
Stopwatch/phone for 6MWT 
 
Markers and a measured corridor/course of known distance for 6MWT and L-test 
 
Chair for L-test and AMPro 
 
Measuring tape 
 
10cm obstacle for AMPro 
 
Qualitative Interview script 
 
The equipment used does not require specific monitoring, maintenance, or calibration procedures.  
 Investigational Device(s) and Comparator(s) 
The subjects will be asked to use the investigational device as their primary prosthesis for 3 weeks. Individual 
exposure will differ between subjects. Subjects are expected to use it for their daily living activities as they would 
with any other prosthesis.  
Subjects will evaluate and provide feedback on their exposure of the comparator prior to them being fitted to the 
investigational device and again after 3 week follow up after completing follow up on the investigational device.  

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The comparator device will be any other passive microprocessor controlled prosthetic knee (excluding 
Kenevo as it does not have the same intended patient population as the investigational device). They have the 
same intended use as the investigational device. Furthermore, they are indicated for the same condition and 
population group. MPKs are widely accepted devices, providing clinical benefits to the user.  
Where possible, the subject will be using the remaining part of their current prosthetic system with the 
investigational device, as it was used with the comparator device. In some cases where a subject is using 
components from other manufacturers (e.g. feet not validated for use with the investigational device) compatible 
components will be provided.  
No other device, medication or intervention will be used. 
For Phase I, 17 subjects are to be enrolled and therefore 20 investigational devices will be used, as the devices 
are intended to be used by a single patient; one for each subject. The number of 20 investigational devices includes 
replacement units in case of failure.  
For Phase II, the number of investigational devices will depend on the sample size, which will determined using 
data from phase I.  
 Subjects  
All subjects will be dispositioned as follows: 
 
Screen Failure: Subject did not pass screening procedures, not called in for clinical visit; 
 
Candidate for enrollment: Passed screening procedures, accepts to come in for clinical visit; 
 
Enrolled: Subject signs informed consent and takes part in the first experimental session; 
 
Fitted: Subject leaves the clinic on the investigational device; 
 
Drop-out: Enrolled subject whose participation ended because they did not want to continue participation. 
 
Discontinued: Candidate for enrollment or Enrolled subject whose participation ended because they 
withdrew consent, were withdrawn by the Investigator, were lost to follow up, or died. 
 
 
 

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 
Write report 
 
Technical support 
 
Conduct Qualitative Interviews 
 
Support with study documentation 
Sponsor Research assistants (SRA) 
 
Technical support 
Local co-investigator 
 
Collect data 
Local Principal Investigator (LPI) 
 
Screen subjects 
 
Explain trial to participants 
 
Responsible for obtaining informed consent from test subjects 
 
Conduct trial procedures at investigators’ site 
 
Collect Data 
 
Fit users with trial device and provide training and back to their current prosthesis 
 
Manage study documentation 
 Study monitoring and Oversight 
The study monitor(s) will monitor the study to ensure all procedures are followed correctly and according to the 
study protocol. The study monitor will gather and review all study data and inform the LPI of missing data or 
nonconformities to the study protocol. 
The study monitor(s) and LPI will maintain communication on a minimum biweekly basis, via telephone and email. 
The LPI will provide the study monitor(s) with information of all scheduled study visits. The study monitor will visit 
each investigational site at least once while a study visit takes place. 
 
 Investigational Device Accountability 
The investigational device will be provided as needed for the study population. Devices will not be packaged but 
will be labeled according to FDA regulatory requirements. Subjects will not be blinded. 
The LPI will keep records documenting the receipt, use and return of the investigational device in the 
Investigational Device Management Form, including: 
 
Date of receipt 
 
ID of each investigational device 
 
Period of use 
 
Subject ID 
 
Date of device return 
 
Date of return of unused, expired or malfunctioning investigational devices, as applicable 
 
 
 

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 Statistical Considerations 
 Statistical design and procedures 
The design will be a non-randomized single group open label prospective repeated measures (ABA). Thereby, 
differences in efficacies of two classes of MPKs are investigated. For each hypothesis (1A1, 1A2, 1B, 1C), 𝑖, the 
population parameter for Rheo Knee 4/Navii, 𝜇௜ଵ is compared to the corresponding population parameter for other 
MPKs, 𝜇௜ଶ. For each research question 𝑖 , the null and hypothesis is 𝐻଴௜: 𝜇௜ଵ= 𝜇௜ଶ, and the alternative hypothesis 
is 𝐻஺௜: 𝜇௜ଵ≠𝜇௜ଶ. Hypotheses are investigated using a Bayesian regression framework. Evidence for 𝐻଴௜ or 𝐻ଵ௜ is 
collected using the posterior distribution of differences in efficacies for each hypothesis. Using the posterior 
distribution, statistical measures as the 89% high density interval (HDI), the percentage in the region of practical 
equivalence (% ROPE), and the probability of direction (PD) will be used to gather evidence for or against each 
hypothesis.  
Acceptance criteria relate to the 89% HDI. An 89% HDI not covering 0 indicates a true difference between the two 
groups. 
For trial phase II, a similar procedure will be performed and uses adjusted priors for model generation. These priors 
will be generated from the posterior distribution of the first trial, therefore making the prior more informative. 
Using bayes theorem, the distribution of differences for each characteristic is represented by the posterior 
distribution and the high density interval will be used. A percentage of 89% for the HDI will be used because it was 
shown to be more stable than the 95% HDI. A specific significance level as in the frequentist approach is not used, 
although the % ROPE is related to a frequentists P value, and therefore a significance level. 
For phase II, Bayesian power analysis will be performed to identify appropriate sample sizes. Sample sizes for 
each group that result in a power >80% are considered to be appropriate. Statistical power will be calculated using 
simulation studies. For any combination of sample sizes, the percentage of simulations where the minimum of the 
HDI will be >0 (therefore indicating a true effect (or difference) between the groups for a specific hypothesis) is 
equal to statistical power.  
Repeated measures analysis has the advantage of increased power vis-à-vis group allocations and reduction in 
error variance associated with induvial difference, as each subject acts as its own control. This is important for 
studying amputees as the group is a small proportion of the total population, and with specific inclusion/exclusion 
criteria the total eligible population becomes very small, making it difficult to find and recruit subjects to attain an 
acceptable level of power. This limited population pool often results in slightly heterogeneous sample, as the 
amputees available are few and far between, in every sense. Furthermore, no single amputation procedure and 
therefore amputated stump is exactly the same, making the experience of each amputee a bit unique. The within-
subject design significantly reduces the individual differences when comparing the two conditions. 
The drawback of the design is the potential of “carryover effects”, i.e. experience from one condition can affect 
outcome or performance in the other condition, creating a confounding extraneous variable that varies with the 
independent variable. Such effects are: practice, positive carryover effect to the latter condition; and fatigue, 
negative carryover effect to the latter condition. 
 Sample size calculation 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

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Total sample size 
= 14 
 
Actual power 
= 
0.9600638  
 
It is therefore expected that 14 subjects are required to complete the protocol with a power of 0,95 and significance 
at 0,05. Effect size was estimated based on previous in-house studies on the previous version of the product for 
the primary end-point.   
Given a drop-out rate of 20%, 17 subjects will be recruited. 
For pass/fail criteria, see Table 4 Endpoints, test methods and hypotheses. 
Phase II: 
Sample size calculations for phase II will be done using data from phase I. 
 Additional statistical matters 
There is no criteria for early termination of the clinical investigation on statistical grounds.  
Any deviations from the statistical plan provided in this protocol will have to be approved by the sponsor and the 
reasons for the deviation reported in the clinical investigational report. Drop-outs and withdrawn participants will 
be included in the data analysis for the procedures that they completed. They will be grouped together and 
compared to the group that finished the protocol. Any statistical differences of the two groups will be reported. If 
the participants have not provided any data, they will not be included in the data analysis. No particular information 
will be excluded from the statistical analysis and tests, as described above. 
 Amendments and Deviations from the Protocol (CIP) 
 Amendments 
Any amendments to this protocol must be first approved by the sponsor and PI, and then be evaluated by the 
overseeing IRB and, where appropriate regulatory authorities, before being implemented. 
For non-substantial changes (e.g. minor logistical or administrative changes, change of monitor(s), telephone 
numbers, renewal of insurance) not affecting the rights, safety and well-being of human subjects or not related to 
the clinical investigation objectives or endpoints, a simple notification to the IRB and, where appropriate, regulatory 
authorities can be sufficient. 
 Deviations 
Investigators are not allowed to deviate from this protocol without a formal approval from the IRB, if the deviation 
affects subject's rights, safety and wellbeing, or the scientific integrity of the clinical investigation. Any such 
deviation from the protocol is to be documented in detail and the report sent to the IRB.  
Under emergency circumstances, deviations from the protocol to protect the rights, safety and well-being of human 
subjects may proceed without prior approval of the sponsor and the IRB. Such deviations shall be documented 
and reported to the sponsor and the IRB as soon as possible. 
Investigators can request for an approval from the sponsor for a deviation if the deviation does not affect subject's 
rights, safety and wellbeing, or the scientific integrity of the clinical investigation. 
In case of a deviation from this protocol taking place without prior approval from the sponsor, and IRB as applicable, 
it shall be reported to the sponsor within 24 hours of LPI knowledge of the deviation. The LPI responsible for the 
deviation is to send a report to the sponsor no later than five days after the deviation was reported. The report shall 
include: 
 
Reason for deviation 

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
When deviation took place

Circumstances of the event

Identification of all subjects affected by the deviation, if any
o
Details how each subject is affected, e.g. rights, safety or wellbeing

Details how this deviation might affect the scientific integrity of the clinical investigation
The sponsor and the IRB will evaluate any deviations that take place without prior approval on a case-by-case 
basis. If the deviation affects subject's rights, safety and/or wellbeing, and the scientific integrity of the clinical 
investigation the LPI shall be disqualified from further participation in the clinical investigation. 
Statement of Compliance
The clinical investigation is sponsored by Össur Iceland ehf. 
It shall be conducted: 

in accordance with the ethical principles that have their origin in the Declaration of Helsinki

in compliance with the ISO 14155
 International Standard 

in compliance with any regional or national legislations, as applicable
The clinical investigation shall not commence until the required approval from the IRB, and regulatory authority as 
applicable, has been obtained. 
Any additional requirements imposed by the IRB or regulatory authority shall be followed, as applicable. 
Ethical Considerations
Anticipated clinical benefits
A patient using the investigational device may or may not benefit clinically from using the device vis-a-vis using 
another microprocessor controlled prosthetic knee (MPK) commercially available. Compared to not using a 
microprocessor controlled prosthetic knee the patient will benefit significantly in terms of mobility and ability to live 
independently. Further on the user will be trained on a new prosthetic component to experience the unprecedented 
functionality of the new component to mitigate the known deficiencies associated with his/her amputation. Within 
the test he/she will be trained on restoring physiological movement pattern closer to those of non-amputees. 
Anticipated benefits include, among others: ramp navigation comparable to other passive MPKs; improved 
standing comfort and perception of safety comparable to other passive MPK. See chapter 6 for details.  
Additionally, the benefit for the user during the testing is that he/she helps in developing a new microprocessor 
controlled prosthetic knee. 
Device related risk
Each device designed and manufactured by Össur is subjected to thorough risk assessment, analysis and control, 
with failure mode effect analysis and hazard analysis, according to PR-00032 Risk Management process, based 
on ISO 14971 
 (Risk Management for Medical Devices). All changes performed to the software and/or functions 
of a device are submitted to multi-level verification and, as applicable, validation processes before being authorized 
for use in a clinical investigation.  
The FMEA and hazard analysis are tools for identifying harms, the sequence of events, their probability, and the 
potential failures that can cause these harms. Anticipated adverse device effects and residual risks associated 
with the investigational device, are identified in the Hazard Analysis Documentation 
 and Chapter 7 in the Clinical 
Investigator´s Brochure 
. 

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- 
Use of the product over the specified maximum life duration. 
- 
User does not read user manual. 
- 
User cannot read user manual. 
- 
User's clinician is insufficiently trained. 
- 
User receives insufficient training from clinician(s). 
- 
Memory failure (user forgets clinicians’ training/advice). 
- 
Nascent Error (user performs well meant "optimization", short-cut or improvisation to unusual 
circumstances). 
- 
User performs activity which subjects  Rheo knee 4/Navii to undue mechanical stress (jumping off a wall 
for example). 
- 
Dropping the  Rheo knee 4/Navii (when removing their prosthesis amputees often lean their prosthesis up 
against a wall which frequently resulting in the limb falling to the ground). 
- 
User does not charge the prosthetic knee. 
- 
User does not have good control over the residual limb. 
 
For a list of foreseeable adverse events and anticipated adverse device effects, together with their likely incidence, 
mitigation or treatment see Chapter 7, and applicable annexes, in the Clinical Investigator´s Brochure 
. 
 Risk of Study (To Patient) 
At each visit a LPI, a certified CPO/CP or clinician, will be present to ensure the safety of the participants. The 
study adds no additional risk other than the risks identified above. Subjects will use the trial device as their primary 
prosthesis in the same manner as they would normally do on their current prosthesis. Thus, they are not required 
to do anything different from their routine clinical visit for acquiring a new MPK (the Navii/Rheo Knee 4 
investigational device) and their daily living activities between study visits. 
 Risk Mitigation 
For each device designed by Össur risk mitigation is part of the design process according to ISO 14971 
 
. 
Furthermore, each participant fitted with the investigational device (Navii/
 
 ) for the first time, will be 
trained by a fully qualified professional until the user can demonstrate sufficient understanding of the product 
operation and demonstrate minimum ability level in its operation. This process is the same as the usual training 
process deployed for normal fitting of a MPK device.  
As part of the training process, the participant will be informed on the risks inherent in using an investigational MPK 
device in an uncontrolled environment. Moreover, the participant will be provided with the product literature (e.g. 
Information for User), as well as being informed and trained on how to use the product. 
 Risk-to-Benefit Rationale 
The residual risks of the investigation and the investigational device are minimal and are significantly out weighted 
by the benefits of participating in the investigation. 
 IRB/REB/REC Review and Communications 
The study protocol (CIP), informed consent form, and other study documentation forms require IRB review and 
approval. Communication to and from the IRB shall be directed from or to the primary Össur contact, the Sponsor 
co-investigator/Monitor. Continuous communication will be maintained between Össur and the IRB, as required. 
Moreover, communication will be maintained between the LPIs and PI and the IRB, as required. 
 Vulnerable populations 
No vulnerable populations will be enrolled.  

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 Informed Consent 
The Local Principal Investigator (LPI) at each site, or any researcher qualified, will obtain from the subject, written 
signed informed consent form to his/her inclusion in the study, after explaining the rationale for and the details of 
the study, the risks and benefits of alternative treatments, and the extent of the subject's involvement. The subject 
will receive a copy of the informed consent.  
The subjects will be informed that their participation is voluntary and that they can withdraw from participation at 
any time, at his/her discretion and this will not have any consequences for the participant’s treatment. 
In case the information on the ICF changes, and subjects need to be provided with new information, the LPI will 
contact each subject by phone and explain the new information as required. If the study must be postponed until 
IRB approval of the amendment is obtained this will be explained to the patient. 
Subjects that for any reason are unable to provide informed consent will not be enrolled in the study. 
 Participant confidentiality – Data management 
a)  Subjects will be assigned a study identification (ID) number. This ID will be used in all relevant 
documentation. Confidentiality of all relevant subject feedback and information will be maintained through use of 
the identifying number only, in all documentation. The study sponsor, Össur, will remain the sole owner of the 
study data.  
Data will be collected and stored either through the Electronic Data Capture (EDS) system Smart-Trial, or via 
paper based CRFs.  
A list connecting the ID to the subject ́s name will be stored either in the Electronic Data Capture (EDS) system 
Smart-Trial or in a locked file with the LPI at each site. Only appropriately qualified individuals designated by the 
Investigator will have access to this information. Access is controlled by password protected accounts. Accounts 
are enabled with designated permissions only. 
b)  Physical source data (e.g. signed Informed Consent forms and paper based forms as applicable) will reside in 
the Local Principal Investigator Site File. This will be physically locked and accessible to the Investigator only. 
c)  Case report forms in Smart-Trial are developed in accordance with this protocol and are quality checked 
against the protocol by the study team before use, the same is true in case of paper-based CRFs. In Smart-Trial, 
validated fields and reference rules are used to control quality of data on entry and where required the order of 
data collection. In case of paper based CRFs they are reviewed by the investigator and a study monitor to 
ensure completeness of data.  
Data that are missing or collected out of timeframe will be flagged. Smart-Trial contains audit history and data 
query functionality, in case of paper based CRFs, data queries are raised by the investigator or study monitor. 
Data queries may be raised ad hoc or at scheduled monitoring visits. Data queries may be reconciled by 
designated individuals (by account permissions in Smart-Trial) only. Where physical records are used these will 
be stored as source data in the investigator site file and attached to Smart Trial forms as scans if applicable. 
e)  In case of electronic data collection; SMART-TRIAL (www.smart-trial.com) will be used as the primary 
Electronic Data Capture tool in this study. SMART-TRIAL is designed and developed in compliance with the 
PIC/S Guidance, PI-011-3 Good Practices for Computerized Systems in Regulated “GxP” Environments, with 
software validation based on IEC 62304. SMART-TRIAL is designed to enable the user to comply with Good 
Clinical Practice (ISO 14155:2020), ICH GCP and other industry requirements, such as FDA 21 CFR Part 11 and 
HIPAA. f) All data in SMART-TRIAL is collected, transferred, and stored encrypted in databases, which are 
hosted on Microsoft Azure ISO certified servers that are managed by SMART-TRIAL within the European Union 
(Dublin, Ireland). Backups are performed continuously throughout the day and stored within the same server. 
Given that Smart-Trial does send messaging to patients in research studies, as part of the informed consent 
process, (as reviewed  by  the  IRB),  patients  will  be  asked  to  consent  to  communications through these 
channels. Smart-Trial is adherent to CAN-SPAM and international equivalents. 

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g)   Photographs and frames in video recordings will only contain as far as possible the lower extremities of 
subjects and any ambulatory assistance provided with their hands only.  Frames containing the face or other 
identifiable features of subjects  will  be  blurred, cropped  or  deleted  if  accidentally  captured.  The data of 
subjects that are withdrawn  from  participation  will  be  retained.  Subjects may request that  their  research  
data  is  delinked  from  their  personally  identifiable data during the course of the study.   
h) In case of EDS, database entry is locked after final patient data is entered. Database is closed and de-
identified data exported by the sponsor Co-investigator/Monitor on completion of close-out monitoring activities 
including resolution of all data queries. Smart Trial audit history is extracted for records of monitoring activities. 
Exported de-identified data is stored on password protected PC intranet for analysis. In case of paper based data 
collection, de-identified data is scanned and shared with the sponsor Co-investigator/Monitor after data collection 
is complete. 
Representatives of the sponsor, sponsor co-investigators and monitors, will be present at the study sites. A 
declaration of confidentiality to be signed by the representatives, ensures necessary data protection. 
i) The data retention period for unlinked clinical data will be a minimum of 5 years in accordance with ISO 
14155:2020. Clinical investigation documents, including but not limited to CIP, CIB, CRFs and clinical 
investigation report(s) should be incorporated into the device technical documentation under the quality 
management system of the manufacturer. 
k)  A Clinical Investigation Report (CIR) will be generated by Össur Medical Office. The report will be stored with 
the device technical file within Össur Quality Management System, along with the unlinked data and all 
accompanying investigational documents, according to the R&D and Quality documentation procedures. 
Subjects participating in the study can have access to the results, on demand, when the CIR is internally 
published.  
Study results, data, and documentation will be stored for a minimum of 5 years.  
 
 

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 Evaluation of Adverse Events and Device Deficiencies 
For a list of foreseeable adverse events and anticipated adverse device effects, together with their likely incidence, 
mitigation or treatment see chapter 13.2 above and 7 in the Clinical Investigator´s Brochure [2].  
 Definitions of adverse events, effects and deficiencies 
An adverse event (AE) is 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. 
An adverse device effect (ADE) is any adverse event related to the use of an investigational medical device, 
including events resulting from insufficient or inadequate instructions for use, operation, malfunction, etc. 
A serious/severe adverse event (SAE) is an AE that: 
 
Is life-threatening or fatal 
 
requires or prolongs hospitalization 
 
results in permanent impairment of a body function 
 
or results in permanent damage to a body structure. 
A serious/severe adverse device effect (SADE) is an adverse device effect that has resulted in any of the 
consequences characteristic of a SAE. 
An anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, severity or 
outcome has been identified in the risk management for the device.  
An unanticipated adverse device effect (UADE) is a serious adverse effect on health or safety of participants 
caused by the device if not previously identified in nature, severity, or degree of incidence in the protocol (CIP) or 
the risk analysis for the device.  
A device deficiency (DD) is the inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance. Device deficiencies include malfunctions, use errors, and inadequate labelling. 
A use error (UE) is an act or omission of an act that results in a different medical device response than intended 
by the manufacturer or expected by the user. 
See ISO 14155 
 for details. 
 Reporting procedures 
All device related adverse events will be investigated. Adverse events that are serious, unanticipated and (possibly) 
device related shall be reported to the sponsor by telephone as soon as possible.  The complete adverse event 
investigation form shall be provided to the sponsor within 24 hrs via email. Within ten days the Sponsor will report 
to the IRB and FDA, as applicable. Any serious device related adverse event will lead to the immediate termination 
of the trial. In this case all participants will be contacted immediately and advised to stop using the investigational 
device. An appointment will be made for them to return the trial device.  
Participants will be provided the contact information of the investigator and told to call them in the event of an 
adverse event. Furthermore, an investigator will contact them weekly to check up on any problems. The 
participants prescribed prosthesis will be kept at the study site while they use the investigational device. If they 
experience problems with the investigational device an appointment will be made with on site to investigate further.  
The investigator shall supply a copy of the complete adverse event investigation form, together with a cover letter 
to the IRB when events are judged to be serious, unanticipated and (possibly) device related.   
Contact in case of unexpected adverse event:  
 
 
 
 
 
 
 
 
Any device deficiencies that did not lead to an adverse event but could have led to a medical occurrence 

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
if either suitable action had not been taken,

if intervention had not been made, or

if circumstances had been less fortunate,
shall be reported according to the same procedure as if an ADE had taken place, specified above. 
Suspension or premature termination of the clinical investigation
The sponsor/principal investigator, the IRBs, and the regulatory authorities can decide about investigation 
continuation. The clinical investigation can be suspended or prematurely terminated if the serious adverse device 
effects are considered disproportionately large compared to the possible benefits of the intervention. If the 
investigation is terminated or suspended all participants will be informed and appropriate follow-up will be assured. 
If sponsor/principal investigator terminates or suspends the investigation the relevant IRBs and regulatory 
authorities will be provided with a detailed written explanation of the termination or suspension. 
The sponsor/principal investigator can upon completion of the analysis of the reason(s) for a suspension decide to 
lift the suspension, when the necessary corrective actions have been implemented. The investigators, IRBs, and 
relevant regulatory authorities will be notified and provided with the relevant data supporting the decision. 
Breaking of blinding will not be relevant in this trial, since group allocation is visible. 
Publication Policy
These results are for internal consumption by Össur employees involved with the project, marketing and for 
regulatory documentation purposes.  
Publication will be pursued if agreed by the Sponsor and Investigator. 

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10. Edwards, M. & Stevens, P. M. Chapter 48: Hip Disarticulation and Hemipelvectomy: Prosthetic Management.
in Atlas of Amputations and Limb Deficiencies 565–573 (American Academy of Orthopaedic Surgeons, 2016)
11. Highsmith, M. J. et al. Safety, energy efficiency, and cost efficacy of the C-Leg for transfemoral amputees: A
review of the literature. Prosthet. Orthot. Int. 34, 362–377 (2010).
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limb amputation: A structured review,” Prosthet. Orthot. Int., vol. 42, no. 6, pp. 652–666, Dec. 2018, doi:
10.1177/0309364618785728.
13. Geertzen, J. et al. Dutch evidence-based guidelines for amputation and prosthetics of the lower extremity:
Rehabilitation process and prosthetics. Part 2. Prosthet. Orthot. Int. 39, 361–371 (2015).
14. Highsmith, M. J. et al. Safety, energy efficiency, and cost efficacy of the C-Leg for transfemoral amputees: A
review of the literature. Prosthet. Orthot. Int. 34, 362–377 (2010).
15. Flood, K. M. et al. Limb deficiency and prosthetic management. 2. Aging with limb loss. Arch. Phys. Med.
Rehabil. 87, S10-14 (2006).
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18. Legro, M. W. et al. Prosthesis evaluation questionnaire for persons with lower limb amputations: assessing
prosthesis-related quality of life. Arch. Phys. Med. Rehabil. 79, 931–938 (1998).
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timed "up & go" test designed for people with lower-limb amputations. Phys Ther. 2005;85(7):626-35.
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