Study setting {9}
SPIRIT guidance: Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained.
The study will be conducted in the Orthopaedic Department at North Shore Hospital, Auckland, New Zealand, which falls under the governance of the Waitemata District Health Board. All patients will have surgery, inpatient stays and follow-up at North Shore Hospital or the Elective Surgery Center, which presides within the hospital campus.
Eligibility criteria {10}
SPIRIT guidance: Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists).
The inclusion criteria are as follows:
- The patient is a male or non-pregnant female between the ages of 40-80 years.
- The patient requires a primary total knee replacement and is indicated for robotic-assisted surgery.
- Patient is deemed appropriate for a cruciate retaining knee replacement.
- The patient has a primary diagnosis of osteoarthritis (OA).
- The patient has intact collateral ligaments.
- The patient is able to undergo CT scanning of the affected limb.
- The patient has signed the study specific, ethics-approved, Informed Consent document.
- The patient is willing and able to comply with the specified pre-operative and post-operative clinical and radiographic evaluations.
The exclusion criteria are as follows:
- The patient has a history of total, unicompartmental reconstruction or fusion of the affected joint.
- Patient has had a previous osteotomy around the knee.
- The patient is morbidly obese (BMI > 41).
- The patient has a deformity which will require the use of stems, wedges or augments in conjunction with the Triathlon Total Knee System.
- The patient has a varus/valgus deformity ≥ 15°.
- The patient has a fixed flexion deformity ≥ 15°.
- The patient has a neuromuscular or neurosensory deficiency, which would limit the ability to assess the performance of the device.
- The patient has a systemic or metabolic disorder leading to progressive bone deterioration.
- The patient is immunologically suppressed or receiving steroids in excess of normal physiological requirements.
- Patient has a cognitive impairment, an intellectual disability or a mental illness.
- The patient is unable to speak English.
- The patient is pregnant.
- The patient has metal hardware present in the region of the hip, knee or ankle (as this is known to create geometrical distortion in the region of the implant).
All patients will be screened by the orthopaedic consultant surgeon and research coordinator based on the criteria. Patients that meet these criteria and express an interest in participating will be provided an ethics approved patient information sheet following initial consultation with their treating doctor. This sheet provides more detail about the study, potential risks, and requirements for follow-up. The research coordinator will assist in scheduling their pre-operative visits if the patient decides to participate in the study. Pre-operative visits include the collection of consent, CT scan, x-rays and completion of patient reported outcomes.
Who will take informed consent? {26a}
SPIRIT guidance: Who will obtain informed consent or assent from potential trial participants or authorized surrogates, and how (see Item 32).
Informed consent will be obtained by either the orthopaedic consultant surgeon or the research coordinator, both of whom are trained in the study requirements and will be appropriately onboarded. Consent will be collected at the pre-operative radiology visit which is scheduled up to 6-months before surgery, but normally occurs within 4 weeks of admission. Māori cultural support is also available as per the New Zealand ethics guidelines.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
SPIRIT guidance: Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable.
Biological specimens are not collected as part of the study protocol and collection of participant data is incorporated into the consent process listed in section 26a.
Interventions
Explanation for the choice of comparators {6b}
SPIRIT guidance: Explanation for choice of comparators.
All participants will undergo robotic arm-assisted TKA to control for surgical induced variability with the technology. MA is defined as the standard surgical technique in TKA, but its standardised approach is hypothesised to be a contributing factor to poorer functional outcome in some patients. FA is an individualised technique in TKA that aims to improve functional outcomes, but this is yet to be proven in an RCT. The high precision of robotic arm-assisted TKA will assist the surgeon in achieving both of the allocated surgical techniques.
Intervention description {11a}
SPIRIT guidance: Interventions for each group with sufficient detail to allow replication, including how and when they will be administered.
All participants will undergo a pre-operative supine CT scan of the lower limb which will be loaded onto the robotic arm-assisted system to assist with planning, soft tissue assessment, ligament balancing and bone resections. In particular, the native bone anatomy will guide the starting implant positions for both MA and FA. Femoral resection landmarks are referenced from the most prominent point of the distal femoral condyles and the most posterior point of the posterior femoral condyles, avoiding osteophytes. Similarly, tibial resection points are placed at the midpoint of each plateau, two-thirds posteriorly in the anteroposterior plane.
All surgeries will be performed using a midline skin incision and a medial parapatellar approach with the femoral and tibial arrays placed extra-articular using bicortical pins. The pre-operative CT scan will be matched to the computer model following a verification process which identifies bony anatomy intra-operatively. The software will identify the hip centre and ankle position to calculate limb alignment. The haptic window defined in the robotic arm-assisted system allows for preservation of a tibial bone island ensuring the posterior cruciate ligament is maintained. All patients will receive a fully cemented Triathlon cruciate retaining implant (Triathlon, Stryker, Kalamazoo, MI, USA) with patella resurfacing. The patella and tibial bearing surfaces will use highly crosslinked polyethylene (X3™, Stryker, Kalamazoo, MI, USA). All procedures will be planned for a 9 mm polyethylene insert allowing for 1 mm adjustments to maximise range of motion and avoid hyperextension or ligament laxity. Femoral and tibial sizing are optimised using the 3D information provided by the CT scan.
For participants randomised to MA, the implant positions will be planned perpendicular to the femoral and tibial mechanical axis and aim to restore a neutral limb alignment (±1°). Femoral component rotation is set to the trans-epicondylar axis whilst the tibial component is aligned to Akagi’s line, which connects the medial border of the patellar tendon to the middle of the posterior cruciate ligament (29). In the sagittal plane, the femoral component is flexed between 0-5° to optimise implant size and prevent notching. The posterior slope is set to 0-3° and a combined flexion limit (tibial + femoral component flexion) of 10° will be applied. Prior to any bone cuts, a manual varus and valgus stress is applied to the joint at 10° and 90° of flexion to provide a virtual gap assessment of ligament tension in the medial and lateral compartment. If balance cannot be achieved, then soft tissue releases will be performed by the surgeon.
For participants randomised to FA, the implant pre-operative plans will position the implants with equal medial and lateral resections of 6.5mm from the subchondral bone of the femoral condyles to replicate the patient’s native anatomy. If present, bone wear is compensated for by adjusting the resection depth by 1-3 mm. Femoral rotation is therefore matched to the posterior condylar axis, and the tibial component is rotated to Akagi’s line. The proximal tibial resections will be set to 7 mm from subchondral bone in both the medial and lateral compartment. In the sagittal plane, the implants are positioned to match the patient’s native flexion and posterior tibial slope. Virtual gap assessment is then performed at 10° and 90° of flexion. The surgeon will then adjust implant position to achieve balance following FA principles (20), within set boundaries imposed on both coronal plane alignment and ligament laxities. Femoral component alignment is limited between 6° of valgus and 3° of varus, whilst tibial component alignment is limited to 6° of varus to 3° of valgus in the coronal plane, with an overall limb alignment target between 6° of varus and 3° of valgus. Gap balance is defined as an equal medial-lateral extension gap and equal gaps in the medial compartment from extension to flexion. A flexion gap differential in the lateral compartment up to 6 mm is permitted, as this represents the native laxity in the lateral flexion compartment and has been associated with improved patient outcomes (30). Further, the implant used in this study is a single radius design and achieving isometric tension of the medial collateral ligament is thought to achieve a more natural pivot. An analytics tool is used to generate all possible balancing solutions based on surgeon defined alignment boundaries and balancing tolerances. A weighted scoring system assists the surgeon to select the optimal component alignment solution. The use of this algorithm also reduces surgical variability between all surgeons. If balance cannot be achieved within these boundaries, then soft tissue releases will be performed by the surgeon.
Intra-operative data will be collected from the robotic arm-assisted system, whilst in-patient rehabilitation data and discharge notes will be collected on the clinical research forms. Participants in both groups will follow the same in-patient post-operative rehabilitation programs and discharge criteria is based on the ability of the patient to mobilise with weight bearing and achieve a range of motion > 90°.
Criteria for discontinuing or modifying allocated interventions {11b}
SPIRIT guidance: Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease).
Both alignment techniques and the robotic arm-assisted system are already used for TKA at the site and the investigating surgeons will have overarching responsibility on the allocation of treatment for each participant. If a knee joint is unable to be satisfactorily balanced following the randomised intervention, then the surgeon may choose to proceed outside this protocol. The participant will then be excluded from the analysis and will follow the standardised care pathway. These patients will be identified as intention to treat in the final analysis.
Strategies to improve adherence to interventions {11c}
SPIRIT guidance: Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return, laboratory tests).
As the intervention relates to surgical technique, all strategies are focused on patient management intra-operatively. Investigating surgeons will be informed of the randomised intervention one day prior to surgery and pre-operative planning will be conducted an hour before analgesia. In the FA group, the final implant positions will be based off soft tissue assessment during the procedure and verified post-operatively using data from the robotic arm-assisted system. In both groups final limb alignments will also be verified using post-operative long leg weight bearing x-rays.
Provisions for post-trial care {30}
SPIRIT guidance: Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial participation.
All participants will continue standard post-operative care with their surgeon at their conclusion of the trial. The sponsor, Stryker New Zealand Ltd, has met the Health and Disability Ethics Committee required for up-to-date insurance for injuries occurring as a result of participation in the trial. Compensation for other injuries will be covered under the New Zealand Accident Compensation Act (2001).
Outcomes {12}
SPIRIT guidance: Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended.
All participants will undergo assessment by the research team pre-operatively, and at 6 weeks, 6 months, 12 months and 24 months post-operatively. The research team will assist in the randomisation process and cannot be blinded to the allocation. The FJS, OKS, IKSS, KOOS, EQ-5D-5L, Net Promoter, BPI, PSQ and VAS pain are all validated clinical assessments of patients undergoing TKA (10,31–37). Physiotherapists will also record functional measures of recovery during in-patient stay and will be blinded to the allocated alignment. The functional measures were selected from recommended list as described by Dobson et al (38) and include: 4 X 10m walk test, passive and active range of motion, 30 second sit-to-stand test and a 3-step stair ascend and descend test. A breakdown of outcome measures is displayed in Table 1.
Participant timeline {13}
SPIRIT guidance: Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see figure at http://www.spirit-statement.org/publications-downloads/).
Participants will be recruited from North Shore Hospital, Auckland and the Elective Surgery Centre, Auckland. Based on other randomised control trials performed at this site (39) this trial aims to recruit 12 patients per month. The recruitment process is estimated to take 22 months and began in November 2020. Results are anticipated in December 2025.
Table 1 Participant evaluation schedule
EVALUATION
|
History /Pre-op
|
Intra-Op
|
In-patients
|
6 weeks
|
6 months
|
12 months
|
24 months
|
Demographics
|
X
|
|
|
|
|
|
|
Medical History
|
X
|
|
|
|
|
|
|
CT scan
|
X
|
|
|
|
|
|
|
Surgical details
|
|
X
|
|
|
|
|
|
Physiotherapy Functional Tests
|
|
|
X
|
X
|
|
|
|
Recovery
|
|
|
|
X
|
|
|
|
BPI
|
X
|
|
X
|
X
|
|
|
|
PSQ
|
X
|
|
|
|
|
|
|
Satisfaction
|
|
|
|
|
X
|
X
|
X
|
Net Promoter
|
|
|
|
|
X
|
X
|
X
|
OKS
|
X
|
|
|
X
|
X
|
X
|
X
|
IKSS
|
X
|
|
|
|
|
|
X
|
FJS-12
|
|
|
|
X
|
X
|
X
|
X
|
KOOS
|
X
|
|
|
|
|
|
X
|
EQ-5D-5L
|
X
|
|
|
X
|
X
|
X
|
X
|
VAS Pain
|
X
|
|
|
X
|
X
|
X
|
X
|
AP and ML X-ray
|
X
|
|
|
|
|
|
X
|
Long Leg X-rays
|
X
|
|
|
|
|
X
|
Sample size {14}
SPIRIT guidance: Estimated number of participants needed to achieve study objectives and how it was determined, including clinical and statistical assumptions supporting any sample size calculations.
This trial seeks to determine if robotic arm-assisted TKA following FA principles provides superior clinical outcomes to robotic arm-assisted TKA following MA principles. Ingelsrud et al. (40) reported that the minimal clinically important change in FJS for TKA patients was 14 points. As there is limited published literature on FA performed with robotic arm-assistance, the power calculations have assumed an effect size of 14, which represents a measure of superiority. A standard deviation of 26 is estimated using the Spearman correlation of 0.61 between the anchor score and change score from patients classified as “somewhat better”, which is also taken as a measure of superiority. Using a power of 80% (β = 0.2), significance level of 5% (α = 0.05) and accounting for 10% loss to follow-up yields a sample size of 120 participants per arm.
Recruitment {15}
SPIRIT guidance: Strategies for achieving adequate participant enrolment to reach target sample size.
This trial includes five high volume arthroplasty surgeons from a large public teaching institution in Auckland. The orthopaedic consultant surgeons and research team will screen potential participants from the hospital waitlist. Participants that meet the eligibility criteria and express interest in participating will be provided with a patient information sheet. The research team will then telephone potential participants to confirm if they would like to enrol in the study. Patients were recruited face-to-face at a radiology appointment and will be recruited remotely during COVID-19 lockdowns.
Assignment of interventions: allocation
Sequence generation {16a}
SPIRIT guidance: Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions.
Participants will be recruited in a block size of 4:1, which aims to maintain balanced treatment arms over time. A master randomisation sequence will be generated prior to the start of the trial using an online random number generator (www.sealedenvelope.com). The master sequence will be maintained by the sponsor and patients will be allocated a treatment in sequential order following consent. The study team and surgeon will be notified of allocation prior to surgery.
Concealment mechanism {16b}
SPIRIT guidance: Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned.
The Sponsor will maintain the master randomisation sequence and will email the allocation treatment to the research team as each patient provides consent to participate in the trial.
Implementation {16c}
SPIRIT guidance: Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions.
The research team will email the Sponsor with the unique de-identified patient study number once a patient has been enrolled. The research team will inform the Investigating surgeons of the randomised intervention one day prior to surgery.
Assignment of interventions: Blinding
Who will be blinded {17a}
SPIRIT guidance: Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how.
The participants and physiotherapists will be blinded to the treatment allocation. All participants will be assigned a unique study number following a consecutive order of consent. The participant identification list will be archived at the site on a secure network in a password-protected file. The investigators and research team are unable to be blinded to the allocation due to their role in the allocation of treatment and execution of surgery.
Procedure for unblinding if needed {17b}
SPIRIT guidance: If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s allocated intervention during the trial.
Participants will be unblinded to the intervention at the end of the trial, unless there is a medical reason to do so prior to the end of the study.
Data collection and management
Plans for assessment and collection of outcomes {18a}
SPIRIT guidance: Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol.
Outcomes will be primarily captured and stored using a password-protected electronic platform (OBERD, Columbia, MO, USA). Participants will be sent automatic email reminders to complete their questionnaires. In the instance of non-compliance, the study coordinators will provide paper case report forms. The physiotherapists are also provided with an instruction manual and equipment to standardise the functional measures, which are collected on paper case report forms.
Plans to promote participant retention and complete follow-up {18b}
SPIRIT guidance: Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols.
Electronic data capture will provide participants with the flexibility to complete the case report forms at their own convenience. Travel compensation for non-standard of care visits such as radiology appointments will also be provided to ensure retention is maintained. Participants who are classified as intent to treat but do not meet the surgical criteria will continue to be followed-up for outcome and safety purposes.
Data management {19}
SPIRIT guidance: Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol.
The International Council for Harmonisation guidelines for Good Clinical Practice (ICH GCP) will be followed throughout the study. The sponsor will conduct routine monitoring visits for data verification against source material, as defined by participant entered data or medical records. Data collected by the sponsor will be stored electronically in a password-protected folder with restricted user access. Periodic surgeon investigator meetings will also be held to review participants where treatment has deviated from the protocol. The chief investigator will be responsible for the training and sign-off of all staff working on the study.
Confidentiality {27}
SPIRIT guidance: How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial.
All research staff and investigators will be employed by the District Health Board and will comply with its confidentiality practices. All participants will be allocated a unique non-identifiable study number and any information disseminated in journals or conferences will ensure patient anonymity is maintained.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
SPIRIT guidance: Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in the current trial and for future use in ancillary studies, if applicable.
There is no planned collection of biological specimens for this study.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
SPIRIT guidance: Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol.
The primary and secondary outcome data gathered from patients in each study group will be pooled and summarised. The mean, standard deviation and 95% confidence intervals will be calculated for each measure in each group. All outcome measures will be assessed on their distribution and homgeneity to confirm the appropriate statistical model. A mixed-effects linear model will be used to compare longitudinal outcomes between the FA TKA (intervention) to the MA TKA (control), with pre-operative measures as a covariate. Adjustments will be made for multiple testing over time. Pairwise comparisons will be examined using a paired t-test if normally distributed, or non-parametric test for skewed distribution. Categorical data will be evaluated using frequency and percent distributions, with significance testing performed using Fisher exact test or Chi-squared test. Statistical significance is defined as a p-value <0.05. Clinical significance will be assessed against the MCID and the PASS as defined in Orr et al (41).
Interim analyses {21b}
SPIRIT guidance: Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial.
Interim analysis will be conducted at milestones of 6-month and 1-year follow-up for dissemination of results. Periodic analysis will also be conducted for patient safety.
Methods for additional analyses (e.g. subgroup analyses) {20b}
SPIRIT guidance: Methods for any additional analyses (eg, subgroup and adjusted analyses).
Sub-group analysis based on patient phenotype will be dependent on sufficient post-hoc sample size calculations.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
SPIRIT guidance: Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation).
A per-protocol and intention to treat analysis will be performed. In the event of randomisation errors, the participant will be converted to the study arm that represents the received treatment. The statistical model will be corrected in the event of missing data and to avoid type I error when performing multiple comparisons.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
SPIRIT guidance: Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code.
The full protocol is described here and will be summarised in future publications. Only the Sponsor and Site will have access to the participant-level dataset.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
Trials guidance: Provide information on the composition, roles and responsibilities of the coordinating centre and trial steering committee and all groups providing day to day support for the trial. There will always be a group running the trial day-to-day and providing organisational support and knowing how often they will meet, plus information on other committees providing oversight such as a Trial Steering Committee, and how often they will meet over the course of the trial, is what we need for item 5d. We do not need names of staff.
SPIRIT guidance: Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data monitoring committee).
The sponsor will routinely monitor the progress of the trial and be responsible for the maintenance of ethics correspondence, governance and compliance documentation and data management. The principal investigator will be responsible for execution of GCP, delegation of authority to research staff and will review adverse events and protocol deviations. A trial steering committee will consist of the principal investigator, co-investigators, research coordinators/assistants and head physiotherapist. Routine meetings will be established to review any major adverse events or protocol deviations. A project sponsor team will also meet quarterly to review progress.
Composition of the data monitoring committee, its role and reporting structure {21a}
SPIRIT guidance: Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed.
The principal investigator will review all adverse event forms for safety assessment. Any device or treatment related adverse events will be reviewed regularly by the Investigator team and a midpoint assessment of patient report outcomes will be conducted.
Adverse event reporting and harms {22}
SPIRIT guidance: Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct.
An adverse event (AE) is defined as any undesirable clinical occurrence in a participant, whether it is considered to be device related or not, that includes a clinical sign, symptom or condition and/or an observation of an unintended technical performance or performance outcome of the device. A serious adverse event (SAE) is an adverse event that results in hospitalisation or prolongation of existing hospitalisation, persistent or significant disability or incapacity, life-threatening, or death. All SAEs will be reported directly to the sponsor after review by the principal investigator for severity, seriousness and relationship to the surgical technique or device. Any event that is potentially associated with the surgical technique or device shall be reported to the local regulatory authority (MedSafe NZ) and the Health and Disability Ethics Committee by the sponsor. All series adverse events will be periodically examined using an alert in the participants electronic medical records and will be reviewed periodically in-line with the evaluation schedule.
Frequency and plans for auditing trial conduct {23}
SPIRIT guidance: Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor.
The sponsor will conduct routine monitoring visits through the duration of the study. Yearly progress reports will be provided to the Northern B Health and Disability Ethics Committee.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
SPIRIT guidance: Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators).
Annual progress reports will be submitted to the Northern B Health and Disability Ethics Committee. Any substantial changes to the protocol or consent will be communicated to participants at their next follow-up visit. All investigators will be informed of future amendments and are required to sign-off on the current version of the protocol.
Dissemination plans {31a}
SPIRIT guidance: Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing arrangements), including any publication restrictions.
The results of this study will be published in peer-reviewed journals and presented at orthopaedic scientific conferences. Authorship will reflect contribution to the study and interpretation of the results. The principal investigator is responsible for dissemination of the results and the sponsor may only review and offer recommendations to the final wording. Participants will be informed about the results of the trial if they have ticked this option in the consent form.