A cross-over, randomised feasibility study of digitally printed versus hand-painted artificial eyes in adults: PERSONAL-EYE-S - a study protocol

Study aims and objectives

The primary aim of this study is to determine the feasibility of conducting a RCT of the effectiveness and cost-effectiveness of digitally-printed artificial eyes compared to hand-painted eyes.

The specific objectives are to:

The feasibility of the future trial will be assessed based on whether:

Study design

The study is a single centre, cross-over, randomised controlled, open feasibility study. Eligible patients who provide written informed consent will be randomised to:

A: receive a digitally-printed artificial eye first (intervention), followed by a hand-painted artificial eye (control); or

B: receive a hand-painted artificial eye first, followed by a digitally-printed artificial eye.

A flow diagram demonstrating participant pathway through the study is provided in Figure 1. Participants will be asked to attend five clinics approximately 2 weeks apart. Clinic 1- final eligibility, consent and baseline data; Clinic 2 – fitting of first eye; Clinic 3 – follow-up data on first eye; Clinic 4 - fitting of second eye; Clinic 5 – follow-up data on second eye and qualitative interviews. Between Clinics 3 and 4, participants can either continue to wear the first allocated eye, or revert to their original artificial eye. No concomitant care or interventions are prohibited (with the exception of participation in other artificial eye studies) and participants are allowed to keep their original artificial eye during the study.

Figure 1. Summary of patient/participant pathway.

All study documents including consent forms and data collection forms can be found as Extended data⁶.

Setting

LAES at Leeds Teaching Hospitals NHS Trust will conduct participant identification, assess eligibility, consent participants and deliver the interventions.

Artificial eyes are classed by the Medicines and Healthcare products Regulatory Agency (MHRA) as "custom-made medical devices" intended for the sole use of a particular patient. Products manufactured in-house in a healthcare establishment that is conducting the study are not subject to the provisions of UK Medical Devices Regulations 2002, provided that the device is being manufactured and used on patients within the sole legal entity. There is no objective/intention to place the device on the market, and we manufacture the device in-house for our own patients within Leeds Teaching Hospitals NHS Trust and therefore in the context of this study, does not constitute a medical devices trial requiring MHRA notification.

Study population

Inclusion criteria

Exclusion criteria

Recruitment

Prospective participants will be identified via three main methods: in clinic, via database screening, or via notification placed on the Royal National Institute of Blind People and Blind Veterans UK websites.

Patients will be handed or posted a study invitation pack containing a Patient Invitation Letter, Participant Information Sheet, a Consent to Contact form, information pack for a close contact, and a pre-paid envelope. Patients will be asked to return the Consent to Contact form to York Trials Unit (YTU) if they wish to be contacted about the trial. Upon receipt of a patient’s Consent to Contact form, YTU will contact them to discuss any queries. The contact details of patients who are willing to be assessed for eligibility will be passed to LAES to arrange an appointment.

Eligibility and consent

Interested patients will be given an appointment to attend clinic for a final eligibility assessment.

Interested patients will be asked to approach a close contact (e.g. friend, family member, spouse), who might be willing to participate alongside the patient, in which case a specific information pack will be provided. Patients can take part without a close contact, but not vice versa.

If eligible and willing, written informed consent will be obtained from patients and, if applicable, their close contacts according to Good Clinical Practice guidelines.

Baseline assessment

Following consent procedures, baseline data will be collected according to the schedule in Table 1.

Eye history and assessment will include past medical history; past ocular and artificial eye history; current medications; and artificial eye socket examination (general socket health, fit and comfort of artificial eye, any current problems).

Randomisation

Following consent and baseline data collection (to ensure allocation concealment), an authorised team member at site will access a secure internet-based service hosted by the UKCRC-accredited YTU to obtain the order of the participant’s treatment allocation. Participants will be randomised on a 1:1 basis using block randomisation. Block sizes will not be disclosed, to ensure concealment. No stratification will be used.

Level of masking

By the nature of the study treatments, masking of participants and clinic staff is not possible and procedure for un-masking is not necessary.

Study treatments

All participants will have an eye socket impression taken for a fitted artificial eye. The artificial eye shape will be made by the LAES maxillofacial laboratory.

Digitally printed artificial eye (Intervention): Digital photos of the unaffected eye will be printed onto specialised adhesive paper pressed onto the artificial eye.

Hand-painted artificial eye (Control): Colour matching the unaffected eye will be done by the imaging department using a colour guide. The artificial eye shape and colour guide number are then sent to iProsthetics (Norwich, UK), to hand-paint and encapsulate with acrylic the artificial eye.

Each eye will be worn for at least two weeks. Attendance at clinics will be facilitated by participants having any travel expenses for additional protocol visits reimbursed. It is hoped this will increase adherence to the protocol in terms of clinic visits. Participants will be able to retain both new artificial eyes following study completion.

Data collection

A summary of all data collection is presented in Table 1.

Feasibility data

Data collected relating to recruitment will be: number of eligible patients, and the proportion of those that were screened: number approached for consent and not approached (and reason why); number approached who provide consent and do not provide consent (and reasons why). In addition, proportion of randomised participants withdrawing (with reasons) and lost to follow-up will be collected (and reason why, where possible).

Staff-collected data and preference questionnaire

Staff will collect data at baseline, Clinic 3 and Clinic 5 which will include information on eye socket health and adverse events (AEs). Data will also be collected at each clinic on tasks undertaken (including manufacturing steps both eyes) and time taken.

Following completion of the study by all participants, the healthcare professionals will also be asked to view eye-band images comparing both eyes, stating which they prefer.

Participant self-reported data

At baseline, Clinic 3 and Clinic 5 the following participant self-reported data will be collected:

Qualitative data collection

Qualitative interviews will be done in the later phases of the study and focus on opinions on trial procedures, the different artificial eyes, delivery times, and patient satisfaction. The study consent form will also contain statements in relation to consent to interview for this qualitative aspect of the study. Re-confirmation of consent will be taken verbally prior to commencement of the interview. A subset of participants (approximately N=15), and their close contacts (approximately N=15) will be interviewed after both artificial eyes have been trialled. Interviews, lasting ~45 minutes, can be done face-to-face at a location of the person’s preference, over the phone, or via video-call and will be audio-recorded. Where possible, individual interviews will be conducted to allow each member of the dyad to freely express their feelings. Data collection will continue until saturation is achieved¹².

Approximately 5 members of the manufacture, ophthalmology, maxillofacial, and prosthetists teams will be invited to take part in a semi-structured interview lasting ~20 minutes. Following consent, interviews will take place face-to-face, over the phone or via videocall.

Close contact data

Close contacts will be asked to complete a study-specific satisfaction questionnaire after their friend/relative has worn each eye (Clinics 3 and 5) and asked to compare photographs of both eyes stating a preference (Clinic 5).

Data management

Data collected as part of this research includes questionnaires, clinical assessments, and qualitative data from interviews. Data will be collected through designed questionnaires on paper which will be scanned using specialist software. The data will be checked against the hard copy of the questionnaire, error checked and then validation checks run against the database. Queries will be raised with the site if discrepancies are identified during validation. A range of centralised monitoring activities (e.g., eligibility, consent, safety checks) will be undertaken as well as regular site visits to discuss any issues being encountered.

Attendance, follow-up and withdrawal

Appointments will be offered approximately 2–3 weeks apart. If a participant is unable to attend a scheduled appointment, they will be offered up to two further appointments within a 6-week period. They must attend Clinics 2 and 4 (the study eye fitting appointments) or will be withdrawn from the trial.

If the participant does not attend Clinics 3 or 5, they and their close contact will be mailed the follow-up questionnaire(s) by YTU. If not returned, they will receive a reminder letter followed by a telephone call.

Participants are free to withdraw from the study at any time and with no obligation to provide a reason. A participant may be withdrawn for clinical reasons (e.g. problems related to eye socket, deterioration in health, distress related to loss of eye etc). If a participant fully withdraws (i.e. withdraws from interventions, questionnaires and interview), their close contact is also withdrawn, but not vice versa.

Storage and confidentiality of data and patient records

Data will be collected through designed questionnaires identified by a unique participant trial number only. The research teams will hold data according to the General Data Protection Regulation (May 2018). Participant details will be stored on a secure password-protected server located at the University of York. Documents will be stored safely in confidential conditions, either physically or electronically and identifiable data will not be stored with questionnaire data. Qualitative interviews sound files and transcripts will be transferred onto a secure server and the data removed from the portable recording device. Data will be archived by the University of York for a minimum period of 5 years following the end of the study.

Adverse events

Adverse events (AEs) and serious AEs (SAEs) will be recorded. Intensity and relationship to the study intervention will be described. Examples of AEs related to participation in this study include: infection, inflammation and irritation, pain/discomfort, prosthesis retention, and implant retention.

Ongoing review of AEs will take place during monthly trial management group (TMG) meetings, discussed with the patient advisory group (PAG) and trial steering committee (TSC) and reported to the sponsor and research ethics committee in line with their guidelines.

Sample size

As this is a feasibility study the primary outcome measure does not inform a sample size calculation. One of the study’s aims is to estimate the within-subject standard deviation for each outcome measure, in order to inform the sample size calculation for a future study. Pilot and feasibility trial literature recommends a sample size of between 24 and 70 to inform reliable estimation of standard deviations^13,14. Thus, we aim to recruit 35 participants, which, assuming a 15% attrition rate, would allow for 30 participants in the final analysis.

Analyses

A statistical analysis plan detailing intended analyses will be drafted before the completion of data collection. The trial will be reported according to the CONSORT guidelines, including the extension to randomised cross-over trials^15–17.

No interim analyses will be conducted. As this is a feasibility trial, no formal stopping rules are in place. At study end, the number of patients screened, eligible, consented and randomised will be summarised. Baseline and outcome data, along with questionnaire return rates and adverse event data, will be summarised overall and by randomised group, and treatment period as appropriate. Within-subject differences for each outcome will also be summarised. To evaluate between-group change in outcome and process variables we will calculate the mean and 95% confidence intervals at baseline, after trialing the first artificial eye, and after trialing the second artificial eye. We will report the number that receive each eye, by group. The number of participants who have a close contact will also be detailed, alongside the return rates for the close contact questionnaires, and associated outcomes.

Continuous variables will be summarised descriptively (mean, standard deviation, median, minimum and maximum) and categorical data will be summarised as counts and percentages. As this is a feasibility trial, statistical hypothesis testing for effectiveness will not be carried out.

The feasibility of undertaking an economic evaluation will be explored; relevant economic data will be identified and corresponding data collection methods investigated. Health outcomes (EQ-5D-5L), healthcare resource use, and costs for patients using the two artificial eye services will be evaluated using descriptive statistics similarly to those described above. Unit costs will be obtained from established costing sources^18,19, taking an NHS perspective. The cost of the eye services will be estimated to indicate the likely resource implications and corresponding costs. A full economic evaluation will not be conducted, though the health economics work, including exploration of missing economic data, will help guide the cost-effectiveness methods used in a full-scale trial.

Transcribed data from the qualitative interviews will be downloaded into NVivo software package, coded and analysed inductively using thematic content analysis^20,21. The researcher conducting the interviews will develop the initial coding framework of themes and subthemes. A second researcher will check a sample of data transcripts against the audio recordings, for accuracy, and will interrogate the validity of the coding against the raw data. The coding framework will be developed iteratively throughout the analysis process, through regular discussions leading to consensus. Detailed thematic summaries will be created using a flexible template that covers the research objectives, while allowing for the emergence of further themes.

Ethical and oversight arrangements

The TMG will monitor the day-to-day management of the trial. Due to the low risk nature of this trial, one independent steering and monitoring committee will set up to undertake the roles traditionally undertaken by the Trial Steering Committee (TSC) and Data Monitoring Committee. Ethical approval was granted by North West – Haydock on 09^th June 2021 (Reference 21/NW/0150). The trial has been registered on ISRCTN (registration number: ISRCTN85921622) on 17^th June 2021. No protocol modifications have been made since ethical approval was obtained (Protocol v2.0_21.05.2021).

Patient and Public Involvement (PPI)

A PAG will contribute to study reports and disseminate findings at appropriate events.

The PAG will include at least four patient members and family members who will meet at critical time-points of the study (approximately every 4 months). Their role will include: assisting with the development of the satisfaction questionnaire; identifying barriers/facilitators to participation; identifying appropriate pathways for dissemination; contribute to the writing of the results lay summary; and, assisting with dissemination events. At least one member of the PAG will sit on the TMG.

Dissemination and projected outputs

Results will be written up and submitted to peer-reviewed journals and presented at relevant national/international ophthalmology conferences. Study findings will be made available to participants, PAG, NHS commissioners and reported on relevant patient-focused websites.

Study status

Data collection, eye manufacturing and clinic attendance are ongoing.