Ototixicity in Patients With a Metal-on-Metal Hip Arthroplasty
Conditions: Ototoxic Hearing Loss, Cobalt Poisoning, Chromium Causing Toxic Effect, Arthroplasty Complications
Sponsor: Reinier Haga Orthopedisch Centrum

OC-2021-012  
 
 Ototoxicity in patients with Metal-on-Metal Hip 
Bearings 
 
 
 
 
 
 
 
 
 
 
 
 
Ototoxicity in patients with Metal-on-Metal hip 
Arthroplasties 
 
 
 
 

OC-2021-012  
 
 Ototoxicity in patients with Metal-on-Metal Hip 
Bearings 
 
 
 
PROTOCOL TITLE: Ototoxicity in patients with Metal-on-Metal hip Arthroplasties 
 
Protocol ID 
OC-2021-012 
Short title 
Ototoxicity with Metal-on-Metal hip bearings 
EudraCT number  
NA 
Version 
3 
Date 
11-07-2022 
Coordinating investigator/project 
leader 
M(aarten).C. Koper 
M.Koper@rhoc.nl 
Principal investigator(s) (in Dutch: 
hoofdonderzoeker/ uitvoerder) 
<Multicenter research: per site> 
Dr N(ina).M.C. Mathijssen 
N.Mathijssen@rhoc.nl 
 
Reinier de Graaf Gasthuis (dept. Orthopedic surgery,  
ENT and Clinical Chemistry )  
Erasmus Medical Center (dept. Orthopedic surgery and 
ENT) 
HAGA Hospital (dept. Orthopedic surgery) 
Zuyderland Ziekenhuis (dept. Orthopedic surgery and 
ENT) 
Reinier Haga Orthopedisch Centrum 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Reinier de Graaf Gasthuis 
Independent expert (s) 
Dr. E. Ronner, Cardioloog RdGG 
 

OC-2021-012  
 
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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Principal Investigator 
Dr. N.M.C. Mathijssen  
 
 
 
11-07-2022 
Coordinating Investigator 
M.C. Koper 
 
11-07-2022 
 
 

OC-2021-012  
 
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Bearings 
 
 
 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................. 7 
2. 
OBJECTIVES ................................................................................................................. 7 
3. 
STUDY DESIGN ............................................................................................................ 8 
4. 
STUDY POPULATION ................................................................................................... 9 
4.1 
Population (base) .................................................................................................... 9 
4.2 
Inclusion criteria ...................................................................................................... 9 
4.3 
Exclusion criteria ..................................................................................................... 9 
4.4 
Sample size calculation ..........................................................................................10  
5. 
METHODS ....................................................................................................................11 
5.1 
Study parameters/endpoints ...................................................................................11 
5.1.1 
Main study parameter/endpoint .......................................................................11 
5.2 
Study procedures ...................................................................................................11 
5.3 
Withdrawal of individual subjects ............................................................................11 
6. 
SAFETY REPORTING ..................................................................................................12 
6.1 
Temporary halt for for reasons of subject safety……………………………………. ..12 
6.2 
AEs and SAEs ........................................................................................................14 
6.2.1 
Adverse events (AEs) ......................................................................................14 
6.2.2 
Serious adverse events (SAEs) .......................................................................14 
6.3 
Follow-up of adverse events ...................................................................................14 
7. 
STATISTICAL ANALYSIS ..........................................................................................15 
8. 
ETHICAL CONSIDERATIONS ...................................................................................15 
8.1 
Regulation statement .............................................................................................15 
8.2 
Recruitment and consent…………………………………………………………………15 
8.3  
Benefits and risks assessment, group relatedness .................................................15 
8.4 
Compensation for injury .........................................................................................15 
9. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................16 
9.1 
Handling and storage of data and documents ........................................................16 
9.2  
Monitoring and Quality Assurance ..........................................................................16 
9.3 
Amendments ..........................................................................................................16 
9.4 
Annual progress report ...........................................................................................16 
9.5 
Temporary halt and (prematurely) end of study report ............................................17 
9.6 
Public disclosure and publication policy ..................................................................17 
10. 
REFERENCES ..........................................................................................................18 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
AE 
Adverse Event 
AR 
Adverse Reaction 
ARMD 
Adverse Reaction to Metal Debris 
Co 
Cr 
ENT 
Cobalt 
Chromium 
Ear, Nose, Throat 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
IC 
Informed Consent 
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
MoM 
Metal-on-Metal  
Sponsor The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Rationale: Patients with a Metal-on-Metal (MoM) hip prosthesis have an increased risk of 
elevated serum metal ions. High plasma levels of cobalt (Co) and chromium (Cr) are 
associated with local and systemic adverse reactions. Ototoxicity, such as hearing loss, 
tinnitus and dizziness, could be related to high plasma levels of these ions. 
Objective: To evaluate the prevalence of ocular-vestibular symptoms in patients with a 
(revised) MoM hip prosthesis. Our hypothesis is that patients with high plasma metal ion levels 
have a higher prevalence of damage to the auditory system.  
Study design: Multi-centre cohort study. 
Study population: All patients with MoM hip arthroplasties implanted in the participating 
clinics (both revised arthroplasties as well as patients with an arthroplasty in situ). 
Intervention (if applicable): A once only non-invasive auditory test, blood samples at the 
outpatient clinic and a questionnaire.  
Main study parameters/endpoints: Auditory test results, levels of Co and Cr in patients with 
MoM hip arthroplasties, subjective hearing loss and general  
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: The burden is primarily time, a questionnaires and one visit to the 
outpatient department. During that visit we will also obtain a blood sample. 
 

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1. INTRODUCTION AND RATIONALE 
 
Many young patients with end stage hip osteoarthritis received hip arthroplasty with a Metal-
on-Metal (MoM) bearing in the mid-2000s. These MoM bearings offered lower wear-rates and 
early return to work and sport activities [1, 2]. However, due to the high revision rates, elevated 
serum cobalt (Co) and chromium (Cr) levels and Adverse Reaction to Metal Debris (ARMD) 
there is a significant decline in use of MoM bearings and in some countries even a prohibition 
[3-5].  
Guidelines in most countries recommend a yearly outpatient control with physical examination 
and determination of plasma metal ion levels. The fact that increased serum metal ions are 
related to local adverse reactions (ARMD) is already proven, however the relationship with 
systemic effects is still unclear. Increased levels of plasma metal ions have been associated 
with different systemic diseases such as peripheral neuropathy, vision loss and hearing loss 
[6-10]. However, no clear relation has been established yet.  
With this study, we aim to investigate the prevalence of ototoxicity (and related hearing loss) 
in patients with a (revised) MoM hip prostheses.    
 
 
2. OBJECTIVES 
 
HYPOTHESIS 
It is hypothesized that patients with an episode or continuous high plasma cobalt or chromium 
levels (parts per billion) have a greater risk of damage to the auditory system, therefore, 
prevalence of ototoxicity (and hearing loss) will be higher in these patients compared to the 
prevalence of ototoxicity (and hearing loss) in patients with low plasma cobalt or chromium 
levels.  
 
Primary objective:  
To assess the prevalence of damage to the auditory system in patients with a Metal-on-Metal 
or revised Metal-on-Metal bearing, especially regarding mid frequency hearing loss. A 
distinction will be made between prevalence in patients with high plasma cobalt or chromium 
levels and patients with low plasma cobalt and chromium levels. A non-invasive, objective 
audiometry test will be obtained and serum metal ion levels will be determined.  
 
Secondary objective(s): 

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To assess which factors are associated with damage to the auditory system (We will only 
perform this if possible, if we have enough cases with hearing loss).  
o Factors of interest: highest known cobalt plasma concentration, highest known 
chromium plasma concentration, type of prosthesis, age, work in a noisy 
environment, presence of ARDM, revision 
o Patients will be asked to complete the hearing questionnaire as well as the 
Metal-on-Metal Prosthesis Questionnaire for Assessing General Health in 
order determine the general health of these patients and subjective hearing 
loss.  
 

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3. STUDY DESIGN 
 
All MoM patients from participating centers will be asked to participate in this study.  
 
After informed consent, we will include the patient and allocate a research number. We will 
send them the questionnaires (online) and make an appointment for the hearing test in the 
participating center. If necessary, the questionnaires can also be completed during the clinic 
visit. During this clinic visit, blood will be obtained to determine the plasma Co and Cr levels.     
 

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4. STUDY POPULATION 
 
4.1 Population  
A total of 462 patients with a MoM hip prosthesis will be contacted.  
 
- 
Reinier de Graaf Gasthuis: 153 patients received a large head MoM total hip prosthesis 
(160 prostheses). 
- 
Erasmus Medical Centre: A total of 63 patients who received a resurfacing MoM hip 
prosthesis.  
- 
HAGA Hospital: a total of 46 patients from received a large head MoM total hip 
prosthesis. 
- 
Zuyderland Hospital: A total of 200 patients of which 143 received a resurfacing MoM 
hip prosthesis (39 bilateral) and 57 patients a large head MoM total hip prosthesis (16 
bilateral).  
 
Note: Patients of Reinier de Graaf Gasthuis and Haga Hospital are operated in that hospital. 
However, follow up might have been performed in Reinier Haga Orthopedic Center (RHOC). 
Therefore, RHOC will also participate in the current study.  
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all the following criteria: 
- 
All MoM patients from the different clinics  
- 
Revision MoM 
- 
Willing to participate 
- 
Speak/write the Dutch language.  
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation 
in this study:  
- 
Not willing to participate 
- 
Previous ENT surgery or ENT pathology 
 
4.4 Sample size calculation 
We did not calculate a sample size since we will ask all MoM patients from the different centres 
to participate in the study.  
 
 

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5. METHODS 
5.1 Study parameters/endpoints 
5.1.1 Main study parameter/endpoint 
Prevalence of damage to the auditory system in patients with a Metal-on-Metal or 
revised Metal-on-Metal bearing, especially regarding mid frequency hearing loss. A 
distinction will be made between prevalence in patients with high plasma cobalt or 
chromium levels and patients with low plasma cobalt and chromium levels.  
5.1.2 
Secondary study parameters/endpoints  
o If possible (if we have enough cases to perform the analysis); factors associated 
with damage to the auditory system in these patients will be determined:  
Factors of interest: highest known cobalt plasma concentration, 
highest known chromium plasma concentration, type of prosthesis, 
age, work in a noisy environment, subjective hearing loss (measured 
with the hearing questionnaire), presence of ARDM, revision 
 
Work in a noisy environment will be determined through a question on 
(prior) work in a noisy environment.  
o Subjective hearing loss and general health. Patients will be asked to complete 
the Amsterdamse questionnaire on hearingloss as well as the Metal-on-Metal 
Prosthesis Questionnaire for Assessing General Health in order determine 
subjective hearing loss and general health of these patients.  
 
5.2 Study procedures 
The physician will contact all patients who are known/operated in the various clinics 
and have a MoM hip prosthesis or revised MoM prosthesis by letter. Patients will 
receive written information on the study and the informed consent. After one week, 
these patients will be contacted by telephone by a member of the research team. These 
patients will be informed about the study and will be invited to participate.  
If the patient agrees to participate, an outpatient clinic appointment will be booked.  
Patients of Haga, RHOC and RdG hospitals will be invited to visit RdG hospital in Delft. 
Patients of EMC or Zuyderland Hospital will visit the outpatient clinic of these hospitals. 
During the outpatient visit, the informed consent will be signed, a hearing test will be  
conducted to every patient by a trained student, nurse or physician. This test includes 
a non-invasive audiological test for about 30 minutes. Furthermore, a blood sample will 
be taken and the patients will be asked to complete a questionnaire, which can be done 
on paper (at the clinic) or online (at home).   
 

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If the hearing test result deviates from ‘normal’, assessed by the software, and related 
to age category, the test results will be reviewed by one of the researchers (DK) in 
Reinier de Graaf Hospital. Results of the hearing tests in the different hospitals are 
comparable regarding standards for ‘normal’ outcomes.  
If the  hearing results need further assessment or treatment the patient will be reviewed 
by the ENT specialist in their hospital.  
If the results from the blood samples defers from the accepted values given by the 
Dutch Orthopedic Association, we will contact the patient and schedule an outpatient 
control appointment with their Orthopedic Surgeon.  
 
In addition, we will also review the patients’ medical history regarding surgery,  
previously measured cobalt/chrome values and whether there has been a previous 
ENT visit or hearing problems.  
The patient data, plasma metal ion levels and hearing test results are collected in a 
Castor database.  
The following data will be collected of each participant: 
Age, gender, cobalt and chromium plasma concentration, highest known cobalt plasma 
concentration, highest known chromium plasma concentration, type of prosthesis, date 
of arthroplasty, work in a noisy environment, subjective hearing loss (measured with 
the hearing questionnaire), presence of ARDM, revision, hearing loss, previous ENT 
visit or hearing problems, general health.  
 
5.3 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences. The investigator can decide to withdraw a subject from the study 
for urgent medical reasons. 

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6. SAFETY REPORTING 
6.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the investigator will suspend the 
study if there is enough ground that continuation of the study will jeopardise subject 
health or safety.  The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 
6.2 AEs and SAEs 
6.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to trial procedure. All adverse 
events reported spontaneously by the subject or observed by the investigator or his 
staff will be recorded. 
6.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in persistent or significant disability or incapacity or; 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
 
The investigator will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for SAEs 
that result in death or are life threatening followed by a period of maximum of 8 days to 
complete the initial preliminary report. All other SAEs will be reported within a period of 
maximum 15 days after the sponsor has first knowledge of the serious adverse events. 
 
6.3 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol  
 
 

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7. STATISTICAL ANALYSIS 
 
Descriptive analysis will be performed for all patient’s data and questionnaires. Statistical 
software (SPSS (IBM SPSS Statistics for Windows)) will be used.  
 
 
Primary outcome 
Prevalence of damage to the auditory system in patients with a Metal-on-Metal or revised 
Metal-on-Metal bearing, especially regarding mid frequency hearing loss will be determined. 
A distinction will be made between prevalence in patients with high plasma cobalt or 
chromium levels and patients with low plasma cobalt and chromium levels.  
 
Groups with and without high plasma serum levels will be compared with a Chi Squared 
test on the absence/presence of hearing loss, for both cobalt as well as chromium.  
 
 
Secondary outcomes 
A logistic regression model will be made to determine factors associated with ototoxicity 
(and related hearing loss). 
Potential predictors are: highest known cobalt plasma concentration, highest known 
chromium plasma concentration, type of prosthesis, age, work in a noisy environment, 
subjective hearing loss (measured with the hearing questionnaire), presence of ARDM, 
revision 
First, a univariable logistic regression model will be performed to identify variables 
significantly associated with the outcome. Variables with p<0.20 will be selected for the 
multivariable model. Then, with backward elimination the model will be made. 
The ROC curve and AUC will used as performance parameters. Goodness-of-fit will be 
determined with the Howmer-Lemeshow test.  
 
If we do not have enough cases of hearing loss, no logistic regression model will be 
made. Instead, descriptive statistics will be performed and both groups will be compared 
with a Mann Whitney U test or Chi Squared test.  
 
 
 
 

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8. ETHICAL CONSIDERATIONS 
8.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki 
(version 7, October 2013) and in accordance with the Medical Research Involving Human 
Subjects Act (WMO). 
 
8.2 Recruitment and consent 
Patients will be sent information on the study by mail. Afterwards, a member of the study 
team will contact the patient by telephone. If the patient is willing to participate, an 
appointment with a member of the study team will be made. At this consultation, details 
about the study will be provided. After the patient decides to participate the informed 
content will be signed. Patients will be given a minimum of 5 days and maximally 21 days 
to consider participation. If a patient wishes more information about this study before 
deciding to participate, the orthopedic surgeon can be consulted. 
 
8.3 Benefits and risks assessment, group relatedness 
There are no risks of benefits associated with participation 
 
8.4 Compensation for injury 
The sponsor/investigator applies for exemption from insurance, since participation in this 
study is without any risk for the patient. The administration of an auditory test is without 
possible injuries or risk.  

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9. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
9.1 Handling and storage of data and documents 
The data is coded and will be handled confidentially. All subjects participating in the 
cohort study will be linked to a subject identification code. This code is based on the order 
of participating patients and the hospital in which the patient visits the outpatient clinic for 
the trial. Each patient receives an individual number. The investigator safeguards the key 
to the code. All data will be stored for 15 years. The handling of personal data will comply 
with the Dutch Personal Data Protection Act. 
All data will be documented in Castor and stored at the network of the Reinier de Graaf 
Hospital, which is safe and of which a backup will be made every day. Patient data will be 
registered in Castor with a subject identification code. The subject identification code will 
be stored locally, at the hospital in which the measurements take place.  
The coordinating researcher of the current study, monitors and the IGJ will have access 
to the source documents. The local research team will have access to the source 
documents of that hospital. Blood samples of all participating centers will be analyzed by 
the Reinier Haga Medisch Diagnostisch Centrum (RHMDC).  
 
 
9.2 Monitoring and Quality Assurance  
Monitoring of the study will be performed by the RdG/RHOC using a risk-based approach. 
Monitoring, among others, includes checking informed consents, in- and exclusion 
criteria, reported serious adverse events and the case report form. The frequency of 
interim monitoring visits (besides one site initiation visit, and one close out visit per study 
site) will be determined by the study’s risk based on a risk classification tool.  
 
 
9.3 Amendments  
Amendments are changes made to the research after a favorable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favorable opinion.  
 
 
9.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  

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9.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last visit.  
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action.  
    
In case the study is ended prematurely, the sponsor will notify the accredited METC 
within 15 days, including the reasons for the premature termination. Within one year after 
the end of the study, the investigator/sponsor will submit a final study report with the 
results of the study, including any publications/abstracts of the study, to the accredited 
METC.   
 
9.6 Public disclosure and publication policy 
This study will be prospectively (i.e. before the first patient is recruited) registered on 
www.clinicaltrials.gov. 
 
 
 
 

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10. REFERENCES 
 
1. Affatato, S., et al., Larger diameter bearings reduce wear in metal-on-metal hip implants. 
Clin Orthop Relat Res, 2007. 456: p. 153-8. 
2. Vale, L., et al., A systematic review of the effectiveness and cost-effectiveness of metal-on-
metal hip resurfacing arthroplasty for treatment of hip disease. Health Technol Assess, 
2002. 6(15): p. 1-109. 
3. Medical Device Alert, All metal-on-metal (MoM) hip replacements: updated advice for 
follow-up of patients. 2017. MDA/2017/018 Issued: 29 June 2017. 
4. Australian Orthopaedic Association National Joint Replacement Registry. 2018. 
5. Dutch Arthroplasty Register (Landelijke Registratie Orthopedische Implantaten). 2018. 
6. Gessner, B.D., et al., A Systematic Review of Systemic Cobaltism After Wear or Corrosion 
of Chrome-Cobalt Hip Implants. J Patient Saf, 2019. 15(2): p. 97-104. 
7. Ikeda, T., et al., Polyneuropathy caused by cobalt-chromium metallosis after total hip 
replacement. Muscle Nerve, 2010. 42(1): p. 140-3. 
8. Jelsma, J., et al., Self-reported systemic complaints in patients with metal-on-metal hip 
arthroplasty. J Orthop, 2020. 18: p. 213-217. 
9. Pelclova, D., et al., Severe cobalt intoxication following hip replacement revision: clinical 
features and outcome. Clin Toxicol (Phila), 2012. 50(4): p. 262-5. 
10. Garcia, M.D., et al., Cobalt toxic optic neuropathy and retinopathy: Case report and review 
of the literature. Am J Ophthalmol Case Rep, 2020. 17: p. 100606.