Study design and randomization
This is a prospective, randomized controlled trial performed at Xi’An AIER eye hospital. The study adheres to the tenets of the Declaration of Helsinki and is registered at the Chinese clinical trial registry (ChiCTR2200055372) and used the SPIRIT reporting guidelines. It was approved by the Xi’An AIER eye hospital ethics committee (AIER-Xian-022001). Inclusion and exclusion criteria are shown in Table 1. Randomization will be performed on the day of surgery using a web-based, online, sealed envelope-based system (https://www.sealedenvelope.com). Specific study information sheets will be provided to patients prior to taking consent. Following a dedicated screening and randomization visit for eligible patients, participants will be randomized to one of two trial arms (Figure 1) and then followed for 18 months at 1, 3, 6, 12 and 18 months. Because of the nature of the intervention, surgeon and participant masking will not be possible, so follow-up measurements are to be performed by masked optometrists.
At baseline all patients were assessed as follows:
- Visual acuity (unaided and corrected), Snellen Chart at a starting distance of 6 meters (m) in both eyes.
- Subjective refraction, both eyes.
- Corneal tomography and corneal center thickness, Scheimpflug imaging (Pentacam) inboth eyes.
- High-order aberration, ray-trace imaging (iTrace) in both eyes.
In the ICL/TICL group, ICL power calculation is performed by the manufacturer in all cases using the proprietary online form (https://evo-ocos.staarag.ch; version 4.08). ICL/TICL size was selected based on anterior chamber depth (Pentacam) and horizontal corneal diameter (Pentacam). After cycloplegia and topical anesthesia are administered, a model V4c ICL/TICL is inserted through a 2.8 mm clear corneal incision at the steepest meridian and the remaining ophthalmic viscosurgical device is completely washed out of the anterior chamber with a balanced salt solution. Postoperatively, nonsteroidal anti-inflammatory drugs (Pranoprofen; Pranopulin, Senju) and antibiotic medications (Levofloxacin; Cravit, Santen) are administered topically 4 times daily for 2 weeks, and the dose is steadily reduced thereafter.
In the SMILE group, the VisuMax 500 KHz femtosecond laser (Visumax, Carl Zeiss Meditec AG) is used to create the femtosecond laser dissection planes for SMILE. The spot distance is 3 mm for lamellar cuts and 2 mm for side-cuts. The spot energy is set to 140 to 150 nJ. The minimum lenticule side-cut thickness is set to 10 mm. The cap diameter is 7.5 mm with a 2.5 mm side-cut and a side-cut angle of 90 degrees. After surgery, patients receive levofloxacin 0.5% eyedrops (Cravit; Santen, Osaka, Japan) and dexamethasone 0.1% eyedrops (Maxidex; Alcon-Couvreur, Puurs, Belgium) 4 times daily for 2 weeks. Artificial tears (HYCOSAN 0.1%; URSAPHARM Arzneimittel GmbH, Saarbrücken,Germany) are prescribed after surgery, and the dosage is adjusted based on the patients’ symptoms.
Outcomes and trial duration
All patients are assessed at baseline, 1, 3, 6, 12 and 18 months. The primary outcome is the refractive predictability at each time points after surgery, which is the proportion of the number of eyes achieving a postoperative spherical equivalent (SE) within ±0.5 D and ±1.0 D of the intended target. Secondary outcomes included
- Unaided visual acuity (UDVA) and best corrected visual acuity (CDVA) following surgery in the study eye using the Snellen chart at a starting distance of 6 m.
- Refraction (measured dioptric spherical equivalent, myopia and astigmatism).
- Refractive astigmatism measured by refraction and corneal astigmatism based on the keratometry readings from the Pentacam corneal topography.
- Quality of vision as assessed by ocular high order aberrations (HOAs) using the iTrace system.
- Changes of corneal endothelial cell count, intraocular pressure and lens vault.
As this is a non-inferiority trial with a binary outcome, we have calculated the required sample size using the maximum likelihood method for large sample. A review of current literature reveal that the reported refractive predictabilities in ICL and SMILE range from 90.0% to 97% and from 93% to 99%, respectively. We therefore assumed the refractive predictabilities in ICL and SMILE in this study are 95% and 97%, respectively. Thus, a sample size of 200 subjects (400 eyes) was deemed to be sufficient to confirm non-inferiority with a power of ≥80% and at a 5% significance level using a 2% non-inferiority margin, which is the clinically significant difference from our preliminary data. To account for a lost to follow-up rate of 30%, 300 subjects are recruited instead of 200.
Patients were first involved in this research at a patient event hosted by Xi’an AIER Eye Hospital. Topics on which opinions were collected included randomization, cross-over and the duration of follow-up of trial patients. The investigators will communicate a summary of the trial results to participants. The burden of the intervention was discussed at our initial meeting with patients and at the consent-taking stage in the trial. All patients will have data collection forms outlining the schedule of each follow-up visit and data to be collected at each visit, which include visual acuity, refraction results, clinical examination and other outcome measures as described above. All data access will be monitored and controlled by the supervisor (Z.W and M.X.W). At the end of the study, the research data will be entered by the research assistant and stored for up to 3 years in compliance with any integrity issues that may arise from any subsequent publications. Following that time period, the data will be kept under the control of the supervisor. The technical appendix, statistical code, and dataset available from the Dryad repository, DOI: 10.5061/dryad.0vt4b8h1g.
Patients are assessed for adverse events during surgery and at all postoperative visits following randomization.
1 Frequency of intraoperative events: for ICL/TICL, adverse events include lens impairment, ICL flip, iris prolapse and hyphema; for SMILE, adverse events include suction loss, opaque bubble layer (OBL), black spots, lenticule remnants and decentration.
2 Frequency of postoperative events: for ICL, we document the frequency of adverse events such as ocular hypertension, transient corneal oedema, corneal endodermis damage, vault abnormality, surgery related-cataract and intraocular infection; for SMILE, we documente the frequency of adverse events such as infectious keratitis, diffuse lamellar keratitis (DLK), Transient Light Sensitivity Syndrome (TLSS), surgery related-cornea ectasia and refractive regression.
All adverse events are reported to both the centralized institution review board and institution heads (AIER Eye Group).
Demographic and baseline information will be described, and eye-specific characteristics will be described for either arm. To study the non-inferiority of ICL to SMILE, a 90% confidence interval (CI) of the difference in predictability between the two treatments (SMILE minus ICL) using a linear mixed model. If the upper limit of the 90% CI does not exceed the pre-defined non-inferiority margin of 2%, non-inferiority is confirmed. Similarly, for each of the two secondary outcomes, efficacy, and safety, a 90% CI of the difference between the two treatments using the above-mentioned method will be constructed and then compared with a non-inferiority margin of 2%. Assuming the other secondary outcome, HOA, follows a normal distribution, a 90% CI of the difference between the two treatments will be constructed through linear mixed model, and then compared with a non-inferiority margin of 2%.