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Central corneal thickness changes in bevel-up versus bevel down phacoemulsification cataract surgery: Study protocol
for a randomised, triple-blind, parallel group trial
Journal: BMJ Open
Manuscript ID bmjopen-2016-012024
Article Type: Protocol
Date Submitted by the Author: 22-Mar-2016
Complete List of Authors: Kaup, Soujanya; Yenepoya Medical College, Yenepoya University, Department of Ophthalmology Shivalli, Siddharudha; Yenepoya Medical College, Yenepoya University,
Department of Community Medicine KS, Divyalakshmi; Yenepoya Medical College, Yenepoya University, Department of Ophthalmology Arunachalam, Cynthia; Yeenepoya Medical College, Yenepoya University, Department of Ophthalmology Varghese, Rejitha; Yenepoya Medical College, Yenepoya University, Department of Ophthalmology
<b>Primary Subject Heading</b>:
Ophthalmology
Secondary Subject Heading: Ophthalmology
Keywords: central corneal thickness, endothelial damage, phaco tip position, phacoemulsification
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ebruary 23, 2020 by guest. Protected by copyright.
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Central corneal thickness changes in bevel-up versus bevel down 1
phacoemulsification cataract surgery: Study protocol for a randomised, 2
triple-blind, parallel group trial 3
Soujanya Kaup1*, Siddharudha Shivalli
2, Divyalakshmi KS
1, Cynthia Arunachalam
1, 4
Rejitha Chinnu Varghese1 5
1Department of Ophthalmology, Yenepoya Medical College, Yenepoya University, 6
Mangalore-575018, India 7
2Department of Community Medicine, Yenepoya Medical College, Yenepoya University, 8
Mangalore-575018, India 9
*Corresponding author: [email protected] 10
11
12
13
14
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16
17
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19
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Central corneal thickness changes in bevel-up versus bevel down 21
phacoemulsification cataract surgery: Study protocol for a randomised, 22
triple-blind, parallel group trial 23
Abstract 24
Introduction: Corneal endothelial damage following phacoemulsification is still one of the 25
major concerns of modern day cataract surgery. Although many techniques have been 26
proposed, the risks of posterior capsular rupture and corneal endothelium damage persist. In 27
theory, damage to the corneal endothelium is minimized by delivering the lowest phaco 28
energy only in the direction necessary to emulsify the lens nucleus. Hence, it is believed, that 29
the bevel of the needle should be turned towards the nucleus or the nuclear fragment (i.e. 30
bevel down. However, there is a difference of opinion among ophthalmologists with 31
reference to the phaco tip position (bevel-up versus bevel down) during phacoemulsification. 32
This subject has not been extensively studied earlier. 33
Methods and analysis: This is a prospective, triple blinded (trial participant, outcome 34
assessor and the data analyst), randomised controlled trial with two parallel groups and with 35
an allocation ratio of 1:1. It will be conducted in a tertiary care hospital, Mangaluru, India. 36
The objective is to compare the post operative central corneal thickness changes between 37
bevel-up and bevel-down techniques of phacoemulsification. Patients aged >18 years with 38
immature cataract undergoing phacoemulsification will be selected for the study. The 39
important exclusion criteria are the history of previous significant ocular trauma or 40
intraocular surgery, corneal pathology, pseudo-exfoliation syndrome, intraocular 41
inflammation, a preoperative fully dilated pupil <6mm, anterior chamber depth <2.5mm and 42
nuclear sclerosis grade ≥4. After randomisation, patients will undergo phacoemulsification 43
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surgery either by bevel-up or bevel-down procedure. With an estimated power of 80%, the 44
calculated sample size is 55 patients in each group. The recruitment will start from April 45
2016. 46
Ethics and dissemination: Yenepoya University Ethics Committee, India has approved the 47
study protocol (YUEC/148/2016 on 18th
Feb, 2016). It complies with the Declaration of 48
Helsinki, local laws and the International Council for Harmonization-good clinical practices. 49
Trial registration number: CTRI/2016/02/006691 50
Key words: central corneal thickness; endothelial damage; phaco tip position; 51
phacoemulsification 52
53
Strengths and limitations of this study: 54
• This study attempts find the most cornea friendly technique of clear corneal 55
phacoemulsification with regard to phaco tip position. 56
• Study findings would be more pertinent to those who are at high risk of corneal 57
decompensation (i.e. small pupil, short anterior chamber depth, high nuclear grade, 58
large nucleus, older age etc.) following phacoemulsification. 59
• Multiple factors can affect the study outcome (central corneal thickness). 60
61
62
63
64
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Introduction 65
Corneal endothelial damage following phacoemulsification is still one of the major concerns 66
of modern day cataract surgery. Introduction of different techniques and certain innovations 67
in the phaco instrumentation have reduced the incidence of post operative corneal endothelial 68
loss. At every stage of cataract surgery, the surgeon has options to optimise corneal 69
endothelial safety. This includes relevant parameters in various phaco platforms, surgical 70
techniques, materials used, and patient characteristics such as grade of the cataract, age of the 71
patient, and the presence of corneal disease. 72
Several mechanisms have been proposed for endothelial cell damage during 73
phacoemulsification; these include mechanical contact with nuclear fragments, irrigation 74
flow, turbulence and movement of fluid, direct trauma caused by instruments or lens 75
fragments, and formation of cavitation bubbles [1,2]. 76
In phacoemulsification procedures the most important predictor of corneal clarity in the early 77
postoperative period is inversely proportional to the amount of ultrasound energy used. For 78
this reason, all of the major platforms now use power modulation to reduce the amount of 79
phaco power necessary, either by varying the duty cycle and pulse energy or by varying the 80
pulse intervals with microburst techniques. 81
Several phacoemulsification techniques have been developed and modified [3–7]. Although 82
many techniques have been proposed, the risks of posterior capsular rupture and corneal 83
endothelium damage persist. In theory, damage to the corneal endothelium is minimized by 84
delivering the lowest phaco energy only in the direction necessary to emulsify the lens 85
nucleus. Furthermore, phacoemulsification should occur in the posterior chamber rather than 86
in the iris plane or the anterior chamber [8]. Hence, it has traditionally been believed, that the 87
bevel of the needle should be turned towards the nucleus or the nuclear fragment (i.e. bevel 88
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down) [9]. However, Faramarzi A et al [10] hypothesize that in the bevel-up technique, the 89
phaco tip, and therefore the source of heat, are farther from the endothelial cells than in the 90
bevel-down technique and this decreases the chance of endothelial cell damage. Further 91
another clinical trial by Raskin E et al. concluded in their study that bevel-up tip position has 92
a negative effect on corneal endothelial cells compared with the bevel-down position [11]. 93
Hence, there is a difference of opinion among ophthalmologists with respect to the phaco tip 94
position during phacoemulsification. This subject has not been extensively studied earlier, 95
hence this study is planned. 96
Objective: To compare the post operative central corneal thickness (CCT) changes between 97
bevel-up and bevel down techniques of phacoemulsification. 98
Trail design: Prospective randomised, parallel group, exploratory, triple-blind (trial 99
participant, outcome assessor and the data analyst) trial with an allocation ratio of 1:1 100
Trial registration: The trial is registered prospectively in Clinical trial registry of India 101
(CTRI/2016/02/006691) and the full trial protocol can accessed on 102
http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=14144&EncHid=&userName=CTRI/2016/103
02/006691 104
Methods 105
Ethics and Dissemination: Yenepoya University Ethics Committee, India has approved the 106
study protocol (YUEC/148/2016 on 18th
Feb 2016). Written informed consent will be taken 107
from all study participants. It complies with the Declaration of Helsinki, local laws and the 108
International Council for Harmonisation- good clinical practices (ICH-GCP). After obtaining 109
the written informed consent (by SK), protected personally identifiable information (PPII) 110
will be replaced by the research identification code. Face sheets containing PPIIs will be 111
removed from the completed questionnaire. Access to master code list will be limited to SK 112
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and DKS. Research data will be stored securely in locked cabinets and the relevant electronic 113
data will be stored in password protected computers and files. The intervention in this trial is 114
the standard treatment for the eligible participants and does not pose additional risk. Hence, 115
the trail participants will not eligible for any damage compensation. Following analysis of the 116
data, the results will be presented in scientific forums and published in scientific journals. 117
Study setting: Department of Ophthalmology, Yenepoya Medical College Hospital, 118
Yenepoya University, Mangaluru, India 119
Study period: January 2016 to December 2017 120
Participants and methods 121
Inclusion criteria: Consecutive patients aged >18 years with immature cataract undergoing 122
phacoemulsification at Yenepoya Medical College Hospital, Mangaluru, India will be 123
selected for the study. 124
Exclusion criteria: History of previous significant ocular trauma or intraocular surgery, 125
corneal pathology, pseudo-exfoliation syndrome, intraocular inflammation, a preoperative 126
fully dilated pupil smaller than 6 mm, anterior chamber depth less than 2.5mm and nuclear 127
sclerosis grade ≥4. Cases with intra-operative complications and patients not willing to 128
participate in the study will be excluded. 129
Interventions (bevel-up and bevel down phacoemuslification groups) 130
Patients will be randomised into 2 groups i.e. bevel up and bevel down group. The phaco tip 131
will be held in the bevel-down position for bevel-down group and in bevel-up position for 132
bevel-up group whenever the phaco tip will be introduced into the anterior chamber. The pre-133
operative evaluation, rest of the surgical procedure, phaco parameters, intra and post-134
operative valuation will remain the same in both the groups. 135
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Pre-operative evaluation: In all cases, a complete preoperative ocular examination will be 136
performed including uncorrected distance visual acuity. (UDVA), corrected distance visual 137
acuity (CDVA), slit lamp evaluation, applanation tonometry, posterior pole evaluation with a 138
noncontact 78 diopter lens, and indirect ophthalmoscopy. The axial length (AL) and anterior 139
chamber depth (ACD) will be measured by ultrasonic A-scan (Echorule Pro, Biomedix 140
Optotechnik & Devices Pvt Ltd.). Central corneal thickness (CCT) will be measured using 141
ultrasound pachymeter (Pacscan 300P, Ver 3 Rev U, Sonomed Inc.). Mean of 5 CCT 142
readings with a standard deviation ≤0.09, with the patient fixating at a target, will be 143
recorded. Nuclear hardness will be evaluated clinically with slit-lamp bio-microscopy 144
according to the colour of the nucleus based on the Lens Opacities Classification System III 145
[12]. 146
Surgical procedure: 147
Two limbal stab incisions will be made. The anterior capsule will be stained with trypan blue 148
dye. After which, the anterior chamber will be filled with hydroxypropyl methylcellulose 2%. 149
A capsulorhexis 5.0 to 5.5 mm in diameter will be created with a needle cystitome. A 2.8 150
mm clear corneal incision will be made, followed by hydrodissection and hydrodelineation of 151
the nucleus. 152
Phacoemulsification of the nucleus will be performed using the phaco chop technique with a 153
30-degree 19-gauge phaco tip. In both groups, the nucleus will be stabilised with the 154
phacoemulsification tip, which is impaled with moderate vacuum and low ultrasonic power. 155
The chopper will be advanced under the anterior capsule until it can pass around the equator 156
of the nucleus at the nucleus-epinucleus border, 180 degree from the phaco tip. The chopper 157
will be advanced towards the phaco tip splitting the nucleus into half. By rotating the lens, 158
several pieces of nucleus are broken (“chopped”). The pieces will then be emulsified. 159
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Following this, irrigation / aspiration of cortical material will be performed with a bimannual 160
irrigation/aspiration cannula. Next, a foldable hydrophilic acrylic intraocular lens with UV 161
absorbing optic and square edge design (Acryfold®, Appasamy ocular devices (P) ltd, 162
Pondicherry, India) will be implanted in the capsular bag using a disposable injector cartridge 163
system. Finally, the anterior chamber will be irrigated, the ocular viscoelastic device will be 164
removed, the wounds will be secured by stromal hydration, and the eye will be patched. 165
Phaco parameters 166
All operations will be performed with Sovereign® compact phacoemulsification system with 167
WhiteStar® technology and Ellips® (Abott Medical Optics, Abbott Laboratories Inc. Abbott 168
Park, Illinois, USA, Inc.). During direct chop, the parameters will be kept as follows: 169
maximum aspiration flow rate: 28 cc/min, maximum vacuum: 295mmHg and threshold 170
vacuum: 125mmHg; maximum power: 40 continuous 6/12 (33%) with Whitestar® on and 171
occluded 40 linear long pulse 6/12 (33%) with Whitestar® on. 172
Intra-operative evaluation: 173
The parameters to be evaluated intra-operatively include mean phaco power (%), effective 174
phaco time (EPT) (seconds) and EFX. The EFX is roughly the EPT with a specific coefficient 175
for the transversal movement of the phaco tip expressed in seconds. Amount of irrigating 176
fluid used will also be noted. 177
Post –op evaluation: 178
All patients will be put on topical ciprofloxacin and dexamethasone eye drops combination 179
one drop 6 times a day for 1 week for the first week, after which it will be gradually tapered 180
over a period of 1 month. All patients will be examined postoperatively on day 1, day 7 and 181
at the end of 1 month. The examinations will include UDVA, CDVA, slitlamp 182
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biomicroscopy, applanation tonometry, fundoscopy, and central corneal thickness. 183
Telephonic reminders will be used to encourage the complete follow-up. 184
Outcome measure: Central corneal thickness on day 1, day 7 and day 30. Deturgescence of 185
the corneal stroma is controlled by the pumping action of the endothelial layer and can be 186
monitored by the measurement of central corneal thickness. Loss or damage of endothelial 187
cells leads to an increase in corneal thickness, which may ultimately induce corneal 188
decompensation and loss of vision [13]. A significant linear correlation exists between 189
increase in corneal thickness in the immediate postoperative period and percentage of 190
endothelial cell loss [14]. Hence CCT measurement can be used as a simple tool to assess the 191
amount of corneal endothelial damage post-cataract surgery. 192
Fig 1 shows the proposed flow of the participants in this trial. 193
Sample size calculation: Sample size calculation is based on the anticipated differences in 194
the CCT (mean± standard deviation) between the two groups. A sample of 50 in each group 195
is needed to detect a mean CCT difference of 20µm with standard deviation of 35.3 [15], 1:1 196
allocation ratio, α error of 0.05 and a power of 80% [16]. The final sample is inflated to 55 197
with due consideration of 10% attrition. 198
Sensitivity analysis of sample size calculation for CCT: The power of the study will be 199
estimated based on the actual number of the study participants who completes the study and 200
the observed differences in CCT across the two study groups. 201
Randomization and blinding 202
SS will generate the random sequence by computer-generated random numbers and it will be 203
concealed in sealed envelopes. SK or DKS will perform the surgeries and RCV will assess 204
the outcome. The trial participants, outcome assessor, and data analyst will be blinded. 205
Data collection and statistical analysis 206
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A detailed statistical analysis plan will be prepared. A blind review of the data will be 207
performed after the end of the planned follow-up period without looking at the randomised 208
treatment for each trail participant. Attrition will be excluded from the analysis. Intention to 209
treat principle will be used for the analysis. Results will be expressed in proportion and 210
means (±standard deviation) for categorical and continuous variables. Chi square and student 211
t tests will be applied to judge the association of CCT with study variables. A repeated 212
measures analysis-of-variance will be conducted to assess for any difference between bevel-213
up and bevel-down groups over time. Data will be analysed using SPSS v16. 214
Data monitoring committee 215
An independent DMC will be established. The DMC will monitor the course of the trail and 216
if necessary will give a recommendation to the main investigator of the trial for 217
discontinuation, modification or continuation of the study. And the same shall be 218
communicated to University ethics Committee and Clinical Trial Registry of India. 219
Safety parameters 220
All the adverse events will be listed and displayed in summary tables. The total number of 221
adverse events, the minimum, maximum and mean number of adverse events per patient will 222
be reported. 223
Study progress 224
The study began in Jan 2016, ethical approval and trial registration number were obtained in 225
Feb 2016. The recruitment will begin in April 2016. 226
Discussion 227
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The importance of preserving the corneal endothelium during intra-ocular surgeries has been 228
well established. Postoperative corneal decompensation is rare when, modern phaco 229
technology is used in combination with proper surgical technique. However, there are several 230
patient-based factors that increase the likelihood of corneal decompensation. With patients 231
electing to have cataract surgery and refractive lens exchange at increasingly younger ages, 232
protecting the endothelial cell layer at all times is essential to avoid the potential for an 233
epidemic of pseudophakic bullous keratopathy (PBK) in the future [17]. Patient expectations 234
after cataract surgery continue to increase, and the patients anticipate perfect vision from as 235
early as the first postoperative day [17]. The main determinant of a patient’s visual acuity on 236
postoperative day 1 is the extent to which the endothelium has been protected [18]. Hence, 237
one must strive to achieve a surgical technique which causes the least damage to the corneal 238
endothelium. This becomes even more imperative while operating on patients who are prone 239
to have a higher endothelial cell loss during phacoemulsification. These include patients with 240
shorter axial length, small pupil, short anterior chamber depth, high nuclear grade, large 241
nucleus, older age etc [19-21]. Hence, in this study an attempt will be made to determine the 242
effect of altering the position of phaco tip (bevel up vs. bevel down) on central corneal 243
thickness. 244
Authors' contributions: SK conceived the study. SK and SS designed the protocol. DKS, 245
CA and RCV revised the protocol. All the authors evaluated the feasibility of this trial in the 246
study setting and gave final approval of this manuscript to be published. 247
Funding statement: 'This research received no specific grant from any funding agency in the 248
public, commercial or not-for-profit sectors. 249
Competing interest: None declared 250
Fig 1 (pdf). Flow diagram for the trial participants 251
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252
References 253
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modern cataract surgery. Surv Ophthalmol. 1999 Oct;44(2):123–47. 255
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damage by air bubbles during phacoemulsification. Arch Ophthalmol. 1997 Jan 257
1;115(1):81–8. 258
3. Kelman CD. Phaco-emulsification and aspiration; a new technique of cataract 259
removal: a preliminary report. Am J Ophthalmol. 1967;64:23–35. 260
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variations. J Cataract Refract Surg. 1991(17):281–91. 262
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Jan;14(1):25–34. 270
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down phaco tip. J Cataract Refract Surg. 2011 Nov;37(11):1971–6. 274
11. Raskin E, Paula JS, Cruz AAV, Coelho RP. Effect of bevel position on the corneal 275
endothelium after phacoemulsification. Arq Bras Oftalmol. 2010 Dec;73(6):508–10. 276
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Bullimore, Ian L. Bailey, et al. The Lens Opacities Classification System III. Arch 278
Ophthalmol. 1993;111:831–6. 279
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and after cataract surgery. Br J Ophthalmol. 2001;85(1):18-20. 281
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and endothelial cell loss. Serial measurements after cataract surgery. Arch 283
Ophthalmol. 1988;106(7):920-2. 284
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corneal thickness in adult South Indians: the Chennai Glaucoma Study. 286
Ophthalmology. 2010 Apr;117(4):700–4. 287
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phacoemulsification/ 294
18. Donnenfeld ED, Holland EJ, Solomon KD, Fiore J, Gobbo A, Prince J, et al. A 295
multicenter randomized controlled fellow eye trial of pulse-dosed difluprednate 296
0.05% versus prednisolone acetate 1% in cataract surgery. Am J Ophthalmol. 2011 297
Oct;152(4):609–17.e1. 298
19. Hayashi K, Hayashi H, Nakao F, Hayashi F. Risk factors for corneal endothelial 299
injury during phacoemulsification. J Cataract Refract Surg. 1996 Oct;22(8):1079–84. 300
20. Walkow T, Anders N, Klebe S. Endothelial cell loss after phacoemulsification: 301
relation to preoperative and intraoperative parameters. J Cataract Refract Surg. 2000 302
May;26(5):727–32. 303
21. Hwang HB, Lyu B, Yim HB, Lee NY. Endothelial Cell Loss after 304
Phacoemulsification according to Different Anterior Chamber Depths. J Ophthalmol. 305
2015;2015:210716. 306
307
308
309
310
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Fig 1. Flow diagram for the trial participants
Invitation to participate in the study is given to patients with
immature cataract
Trial information is given to potential participants
Assessment of eligibility
based on inclusion/
exclusion criteria
Complete baseline evaluation
Randomisation
Phaco-emulsification with bevel
up position
Phaco-emulsification with bevel
down position
Post op Day 1 evaluation Post op Day 1 evaluation
Post op Day 7 evaluation Post op Day 7 evaluation
Post op Day 30 evaluation Post op Day 30 evaluation
Loss of follow-up or discontinued
Informed Consent
Exclude: No
informed consent
Exclude:
H/O previous ocular trauma
Intraocular surgery
Corneal pathology
Pseudoexfoliation Intraocular
inflammation
Dilated pupil < 6 mm
ACD < 2.5mm
Nuclear sclerosis grade ≥4
Intra-operative complications
Allocate into group 1: Bevel
up(n=55)
Allocate into group 2: Bevel
down(n=55)
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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*
Section/item Item No
Description Line number
Administrative information
Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym 21-23
Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry 50
2b All items from the World Health Organization Trial Registration Data Set 101-04
Protocol version 3 Date and version identifier 101-04
Funding 4 Sources and types of financial, material, and other support 248-49
Roles and
responsibilities
5a Names, affiliations, and roles of protocol contributors 4-10, 245-47
5b Name and contact information for the trial sponsor NA
5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and
interpretation of data; writing of the report; and the decision to submit the report for publication, including
whether they will have ultimate authority over any of these activities
NA
5d 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)
NA
Introduction
Background and
rationale
6a Description of research question and justification for undertaking the trial, including summary of relevant
studies (published and unpublished) examining benefits and harms for each intervention
66-96
6b Explanation for choice of comparators 84-96
Objectives 7 Specific objectives or hypotheses 97-98
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2
Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group),
allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)
99-100
Methods: Participants, interventions, and outcomes
Study setting 9 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
118-119
Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and
individuals who will perform the interventions (eg, surgeons, psychotherapists)
121-29
Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be
administered
130-72
11b 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)
NA: One time
intervention
11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence
(eg, drug tablet return, laboratory tests)
NA: One time
intervention
11d Relevant concomitant care and interventions that are permitted or prohibited during the trial NA
Outcomes 12 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
185-92
Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits
for participants. A schematic diagram is highly recommended (see Figure)
193, Fig 1
Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including
clinical and statistical assumptions supporting any sample size calculations
194-98
Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size 122
Methods: Assignment of interventions (for controlled trials)
Allocation:
Sequence
generation
16a 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
203-04
Allocation
concealment
mechanism
16b 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
203-04
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Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to
interventions
203-04
Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome
assessors, data analysts), and how
205
17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s
allocated intervention during the trial
NA
Methods: Data collection, management, and analysis
Data collection
methods
18a 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
206-14
18b 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
184
Data management 19 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
NA: single center
trial with relatively
small sample
Statistical methods 20a 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
207-14
20b Methods for any additional analyses (eg, subgroup and adjusted analyses) 207-14
20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any
statistical methods to handle missing data (eg, multiple imputation)
NA
Methods: Monitoring
Data monitoring 21a 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
215-19
21b 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
NA
Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse
events and other unintended effects of trial interventions or trial conduct
220-23
Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent
from investigators and the sponsor
216-19
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4
Ethics and dissemination
Research ethics
approval
24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval 106-10
Protocol
amendments
25 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)
218-19
Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and
how (see Item 32)
109-10
26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary
studies, if applicable
NA
Confidentiality 27 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
110-13
Declaration of
interests
28 Financial and other competing interests for principal investigators for the overall trial and each study site 248-50
Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that
limit such access for investigators
112-13
Ancillary and post-
trial care
30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial
participation
114-16
Dissemination
policy
31a 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
NA
31b Authorship eligibility guidelines and any intended use of professional writers Author sequence
will be decided
based on the
contributions of all
the investigators
31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code NO
Appendices
Informed consent
materials
32 Model consent form and other related documentation given to participants and authorised surrogates Sup file 1
Biological
specimens
33 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
NA
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*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.
Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons
“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.
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Central corneal thickness changes in bevel-up versus bevel down phacoemulsification cataract surgery: Study protocol
for a randomised, triple-blind, parallel group trial
Journal: BMJ Open
Manuscript ID bmjopen-2016-012024.R1
Article Type: Protocol
Date Submitted by the Author: 25-Aug-2016
Complete List of Authors: Kaup, Soujanya; Yenepoya Medical College, Yenepoya University, Department of Ophthalmology Shivalli, Siddharudha; Yenepoya Medical College, Yenepoya University,
Department of Community Medicine KS, Divyalakshmi; Yenepoya Medical College, Yenepoya University, Department of Ophthalmology Arunachalam, Cynthia; Yeenepoya Medical College, Yenepoya University, Department of Ophthalmology Varghese, Rejitha; Yenepoya Medical College, Yenepoya University, Department of Ophthalmology
<b>Primary Subject Heading</b>:
Ophthalmology
Secondary Subject Heading: Ophthalmology
Keywords: central corneal thickness, endothelial damage, phaco tip position, phacoemulsification
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1
Central corneal thickness changes in bevel-up versus bevel down 1
phacoemulsification cataract surgery: Study protocol for a randomised, 2
triple-blind, parallel group trial 3
Soujanya Kaup1*, Siddharudha Shivalli
2, Divyalakshmi KS
1, Cynthia Arunachalam
1, 4
Rejitha Chinnu Varghese1 5
1Department of Ophthalmology, Yenepoya Medical College, Yenepoya University, 6
Mangalore-575018, India 7
2Department of Community Medicine, Yenepoya Medical College, Yenepoya University, 8
Mangalore-575018, India 9
*Corresponding author: [email protected] 10
11
12
13
14
15
16
17
18
19
20
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Central corneal thickness changes in bevel-up versus bevel down 21
phacoemulsification cataract surgery: Study protocol for a randomised, 22
triple-blind, parallel group trial 23
Abstract 24
Introduction: Corneal endothelial damage following phacoemulsification is still one of the 25
major concerns of modern day cataract surgery. Although many techniques have been 26
proposed, the risks of posterior capsular rupture and corneal endothelium damage persist. In 27
theory, damage to the corneal endothelium is minimized by delivering the lowest phaco 28
energy only in the direction necessary to emulsify the lens nucleus. Hence, it is believed, that 29
the bevel of the needle should be turned towards the nucleus or the nuclear fragment (i.e. 30
bevel down. However, there is a difference of opinion among ophthalmologists with 31
reference to the phaco tip position (bevel-up versus bevel down) during phacoemulsification. 32
This subject has not been extensively studied earlier. 33
Methods and analysis: This is a prospective, triple blinded (trial participant, outcome 34
assessor and the data analyst), randomised controlled trial with two parallel groups and with 35
an allocation ratio of 1:1. It will be conducted in a tertiary care hospital, Mangaluru, India. 36
The objective is to compare the post operative central corneal thickness changes between 37
bevel-up and bevel-down techniques of phacoemulsification. Patients aged >18 years with 38
immature cataract undergoing phacoemulsification will be selected for the study. The 39
important exclusion criteria are the history of previous significant ocular trauma or 40
intraocular surgery, corneal pathology, pseudo-exfoliation syndrome, intraocular 41
inflammation, a preoperative fully dilated pupil <6mm, anterior chamber depth <2.5mm and 42
nuclear sclerosis grade ≥4. After randomisation, patients will undergo phacoemulsification 43
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surgery either by bevel-up or bevel-down procedure. With an estimated power of 80%, the 44
calculated sample size is 55 patients in each group. The recruitment will start from April 45
2016. 46
Ethics and dissemination: Yenepoya University Ethics Committee, India has approved the 47
study protocol (YUEC/148/2016 on 18th
Feb, 2016). It complies with the Declaration of 48
Helsinki, local laws and the International Council for Harmonization-good clinical practices. 49
Trial registration number: CTRI/2016/02/006691 50
Key words: central corneal thickness; endothelial damage; phaco tip position; 51
phacoemulsification 52
53
Strengths and limitations of this study: 54
• This study attempts find the most cornea friendly technique of clear corneal 55
phacoemulsification with regard to phaco tip position. 56
• Study findings would be more pertinent to those who are at high risk of corneal 57
decompensation (i.e. small pupil, short anterior chamber depth, high nuclear grade, 58
large nucleus, older age etc.) following phacoemulsification. 59
• Multiple factors can affect the study outcome (central corneal thickness). 60
61
62
63
64
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Introduction 65
Corneal endothelial damage following phacoemulsification is still one of the major concerns 66
of modern day cataract surgery. Introduction of different techniques and certain innovations 67
in the phaco instrumentation have reduced the incidence of post operative corneal endothelial 68
loss. At every stage of cataract surgery, the surgeon has options to optimise corneal 69
endothelial safety. This includes relevant parameters in various phaco platforms, surgical 70
techniques, materials used, and patient characteristics such as grade of the cataract, age of the 71
patient, and the presence of corneal disease. 72
Several mechanisms have been proposed for endothelial cell damage during 73
phacoemulsification; these include mechanical contact with nuclear fragments, irrigation 74
flow, turbulence and movement of fluid, direct trauma caused by instruments or lens 75
fragments, and formation of cavitation bubbles [1,2]. 76
In phacoemulsification procedures the most important predictor of corneal clarity in the early 77
postoperative period is inversely proportional to the amount of ultrasound energy used. For 78
this reason, all of the major platforms now use power modulation to reduce the amount of 79
phaco power necessary, either by varying the duty cycle and pulse energy or by varying the 80
pulse intervals with microburst techniques. 81
Several phacoemulsification techniques have been developed and modified [3–7]. Although 82
many techniques have been proposed, the risks of posterior capsular rupture and corneal 83
endothelium damage persist. In theory, damage to the corneal endothelium is minimized by 84
delivering the lowest phaco energy only in the direction necessary to emulsify the lens 85
nucleus. Furthermore, phacoemulsification should occur in the posterior chamber rather than 86
in the iris plane or the anterior chamber [8]. Hence, it has traditionally been believed, that the 87
bevel of the needle should be turned towards the nucleus or the nuclear fragment (i.e. bevel 88
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down) [9]. However, Faramarzi A et al [10] hypothesize that in the bevel-up technique, the 89
phaco tip, and therefore the source of heat, are farther from the endothelial cells than in the 90
bevel-down technique and this decreases the chance of endothelial cell damage. Further 91
another clinical trial by Raskin E et al. concluded in their study that bevel-up tip position has 92
a negative effect on corneal endothelial cells compared with the bevel-down position [11]. 93
Hence, there is a difference of opinion among ophthalmologists with respect to the phaco tip 94
position during phacoemulsification. This subject has not been extensively studied earlier, 95
hence this study is planned. 96
Objective: To compare the post operative central corneal thickness (CCT) changes between 97
bevel-up and bevel down techniques of phacoemulsification. 98
Trail design: Prospective randomised, parallel group, exploratory, triple-blind (trial 99
participant, outcome assessor and the data analyst) trial with an allocation ratio of 1:1 100
Trial registration: This trial is registered prospectively in Clinical trial registry of India 101
(CTRI/2016/02/006691) and the full trial protocol can accessed on 102
http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=14144&EncHid=&userName=CTRI/2016/103
02/006691 104
Methods 105
Ethics and Dissemination: Yenepoya University Ethics Committee, India has approved the 106
study protocol (YUEC/148/2016 on 18th
Feb 2016). Written informed consent will be taken 107
from all study participants. It complies with the Declaration of Helsinki, local laws and the 108
International Council for Harmonisation- good clinical practices (ICH-GCP). After obtaining 109
the written informed consent (by SK), protected personally identifiable information (PPII) 110
will be replaced by the research identification code. Face sheets containing PPIIs will be 111
removed from the completed questionnaire. Access to master code list will be limited to SK 112
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and DKS. Research data will be stored securely in locked cabinets and the relevant electronic 113
data will be stored in the password-protected computers and files. The intervention in this 114
trial is the standard treatment for the eligible participants and does not pose an additional risk. 115
Hence, the trial participants will not be eligible for any damage compensation. Following 116
analysis of the data, the results will be presented in scientific forums and published in 117
scientific journals. 118
Study setting: Department of Ophthalmology, Yenepoya Medical College Hospital, 119
Yenepoya University, Mangaluru, India 120
Study period: January 2016 to December 2017 121
Participants and methods 122
Inclusion criteria: Consecutive patients aged >18 years with immature cataract undergoing 123
phacoemulsification at Yenepoya Medical College Hospital, Mangaluru, India will be 124
selected for the study. 125
Exclusion criteria: History of previous significant ocular trauma or intraocular surgery, 126
corneal pathology, pseudoexfoliation syndrome, intraocular inflammation, a preoperative 127
fully dilated pupil smaller than 6 mm, anterior chamber depth less than 2.5mm, and nuclear 128
sclerosis grade >4. Cases with intra-operative complications, those were direct chop could 129
not be done and patients not willing to participate in the study will be excluded. 130
Interventions (bevel-up and bevel down phacoemuslification groups) 131
Patients will be randomised into two groups i.e. bevel up and bevel down. The phaco tip will 132
be held in the bevel-down position for bevel-down group and in bevel-up position for bevel-133
up group whenever the phaco tip is introduced into the anterior chamber. The pre-operative 134
evaluation, rest of the surgical procedure, phaco parameters, intra-, and post-operative 135
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evaluation will remain the same in both the groups. All the surgeries will be performed by a 136
single surgeon (SK). 137
Pre-operative evaluation: In all the cases, a complete preoperative ocular examination will 138
be performed including uncorrected distance visual acuity. (UDVA), corrected distance 139
visual acuity (CDVA), slit lamp evaluation, applanation tonometry, posterior pole evaluation 140
with a noncontact 78 diopter lens, and indirect ophthalmoscopy. The axial length (AL) and 141
anterior chamber depth (ACD) will be measured by ultrasonic A-scan (Echorule Pro, 142
Biomedix Optotechnik & Devices Pvt Ltd.). Central corneal thickness (CCT) will be 143
measured using ultrasound pachymeter (Pacscan 300P, Ver 3 Rev U, Sonomed Inc.). The 144
mean of 5 CCT readings with a standard deviation ≤0.09, with the patient fixating at a target, 145
will be recorded. Nuclear hardness will be evaluated clinically with slit-lamp biomicroscopy 146
according to the colour of the nucleus based on the Lens Opacities Classification System III 147
[12]. 148
Surgical procedure: 149
Two limbal stab incisions will be made. The anterior capsule will be stained with trypan blue 150
dye. After which, the anterior chamber will be filled with hydroxypropyl methylcellulose 2%. 151
A capsulorhexis 5.0 to 5.5 mm in diameter will be created with a needle cystitome. A 2.8 152
mm clear corneal incision will be made, followed by hydrodissection and hydrodelineation of 153
the nucleus. 154
Phacoemulsification of the nucleus will be performed using the phaco chop technique with a 155
30-degree 19-gauge phaco tip. In both groups, the nucleus will be stabilised with the 156
phacoemulsification tip, which is impaled with moderate vacuum and low ultrasonic power. 157
The chopper will be advanced under the anterior capsule until it can pass around the equator 158
of the nucleus at the nucleus-epinucleus border, 180 degree from the phaco tip. The chopper 159
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will be advanced towards the phaco tip splitting the nucleus into half. By rotating the lens, 160
several pieces of nucleus are broken (“chopped”). The pieces will then be emulsified. 161
Following this, irrigation / aspiration of cortical material will be performed with a bimannual 162
irrigation/aspiration cannula. Next, a foldable hydrophilic acrylic intraocular lens with UV 163
absorbing optic and square edge design (Acryfold®, Appasamy ocular devices (P) ltd, 164
Pondicherry, India) will be implanted in the capsular bag using a disposable injector cartridge 165
system. Finally, the anterior chamber will be irrigated, the ocular viscoelastic device will be 166
removed, the wounds will be secured by stromal hydration, and the eye will be patched. 167
Phaco parameters 168
All the operations will be performed with Sovereign® compact phacoemulsification system 169
with WhiteStar® technology and Ellips® (Abott Medical Optics, Abbott Laboratories Inc. 170
Abbott Park, Illinois, USA, Inc.). During direct chop, the parameters will be kept as follows: 171
maximum aspiration flow rate: 28 cc/min, maximum vacuum: 295mmHg and threshold 172
vacuum: 125mmHg; maximum power: 30 continuous 6/12 (33%) with Whitestar® on and 173
occluded 40 linear long pulse 6/12 (33%) with Whitestar® on. The parameters for higher 174
grades of cataract will be as follows: maximum aspiration flow rate: 28 cc/min, maximum 175
vacuum: 400mmHg and threshold vacuum 250mmHg; maximum power: 40 continuous 6/12 176
(33%) with Whitestar® on and occluded 40 linear long pulse 6/12 (33%) with Whitestar® on. 177
Intra-operative evaluation: 178
The parameters to be evaluated intra-operatively include mean phaco power (%), effective 179
phaco time (EPT) (seconds) and EFX. The EFX is roughly the EPT with a specific coefficient 180
for the transversal movement of the phaco tip expressed in seconds. Amount of irrigating 181
fluid used will also be noted. 182
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Post –op evaluation: 183
All the patients will be put on topical ciprofloxacin and dexamethasone eye drops 184
combination one drop 6 times a day for 1 week for the first week, after which it will be 185
gradually tapered over a period of 1 month. All the patients will be examined postoperatively 186
on day 1, day 7, and at the end of 1 month. The examinations will include UDVA, CDVA, 187
slitlamp biomicroscopy, applanation tonometry, fundoscopy, and central corneal thickness. 188
Telephonic reminders will be used to encourage the complete follow-up. 189
Outcome measure: The central corneal thickness on day 1, day 7, and day 30. 190
Deturgescence of the corneal stroma is controlled by the pumping action of the endothelial 191
layer and can be monitored by the measurement of central corneal thickness. Loss or damage 192
of endothelial cells leads to an increase in corneal thickness, which may ultimately induce 193
corneal decompensation and loss of vision [13]. A significant linear correlation exists 194
between increase in corneal thickness in the immediate postoperative period and percentage 195
of endothelial cell loss [14]. Hence, CCT measurement can be used as a simple tool to assess 196
the amount of corneal endothelial damage post-cataract surgery. 197
Fig 1 shows the proposed flow of the participants in this trial. 198
Sample size calculation: The sample size calculation is based on the anticipated differences 199
in the CCT (mean± standard deviation) between the two groups. A sample of 50 in each 200
group is needed to detect a mean CCT difference of 20µm with a standard deviation of 35.3 201
[15], 1:1 allocation ratio, α error of 0.05 and a power of 80% [16]. The final sample is 202
inflated to 55 with due consideration of 10% attrition. 203
Sensitivity analysis of sample size calculation for CCT: The power of the study will be 204
estimated based on the actual number of the study participants who complete the study and 205
the observed differences in CCT across the two study groups. 206
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Randomization and blinding 207
SS will generate the random sequence by computer-generated random numbers and it will be 208
concealed in sealed envelopes. SK will perform the surgeries and RCV will assess the 209
outcome. The trial participants, outcome assessor, and data analyst will be blinded. 210
Data collection and statistical analysis 211
A detailed statistical analysis plan will be prepared. A blind review of the data will be 212
performed after the end of the planned follow-up period without looking at the randomised 213
treatment for each trail participant. Attritions will be excluded from the analysis. Intention to 214
treat principle will be used for the analysis. Results will be expressed in proportion and 215
means (±standard deviation) for categorical and continuous variables, respectively. Student t 216
test will be used to compare CCTs between the study groups. A repeated measures analysis-217
of-variance will be conducted to assess for any difference in CCT between bevel-up and 218
bevel-down groups over time. All the data will be analysed using SPSS v16. 219
Data monitoring committee 220
An independent DMC will be established. The DMC will monitor the course of the trial and 221
if necessary will give a recommendation to the main investigator of the trial for 222
discontinuation, modification or continuation of the study. And the same shall be 223
communicated to the University ethics Committee and Clinical Trial Registry of India. 224
Safety parameters 225
All the adverse events will be listed and displayed in summary tables. The total number of 226
adverse events, the minimum, maximum and mean number of adverse events per patient will 227
be reported. 228
Study progress 229
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The study began in Jan 2016, ethical approval and trial registration number were obtained in 230
Feb 2016. The recruitment will begin in April 2016. 231
Discussion 232
The importance of preserving the corneal endothelium during intra-ocular surgeries has been 233
well established. Postoperative corneal decompensation is rare when, modern phaco 234
technology is used in combination with proper surgical technique. However, there are several 235
patient-based factors that increase the likelihood of corneal decompensation. With patients 236
electing to have cataract surgery and refractive lens exchange at increasingly younger ages, 237
protecting the endothelial cell layer at all times is essential to avoid the potential for an 238
epidemic of pseudophakic bullous keratopathy (PBK) in the future [17]. Patient expectations 239
after cataract surgery continue to increase, and the patients anticipate perfect vision from as 240
early as the first postoperative day [17]. The main determinant of a patient’s visual acuity on 241
postoperative day 1 is the extent to which the endothelium has been protected [18]. Hence, 242
one must strive to achieve a surgical technique which causes the least damage to the corneal 243
endothelium. This becomes even more imperative while operating on patients who are prone 244
to have a higher endothelial cell loss during phacoemulsification. These include patients with 245
shorter axial length, small pupil, short anterior chamber depth, high nuclear grade, large 246
nucleus, older age etc [19-21]. Hence, in this study an attempt will be made to determine the 247
effect of altering the position of phaco tip (bevel up vs. bevel down) on central corneal 248
thickness. 249
Authors' contributions: SK conceived the study. SK and SS designed the protocol. DKS, 250
CA and RCV revised the protocol. All the authors evaluated the feasibility of this trial in the 251
study setting and gave final approval of this manuscript to be published. 252
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Funding statement: This research received no specific grant from any funding agency in the 253
public, commercial or not-for-profit sectors. 254
Competing interest: None declared 255
Fig 1 (pdf). Flow diagram for the trial participants 256
257
References 258
1. Linebarger EJ, Hardten DR, Shah GK, Lindstrom RL. Phacoemulsification and 259
modern cataract surgery. Surv Ophthalmol. 1999 Oct;44(2):123–47. 260
2. Kim EK, Cristol SM, Geroski DH, McCarey BE, Edelhauser HF. COrneal endothelial 261
damage by air bubbles during phacoemulsification. Arch Ophthalmol. 1997 Jan 262
1;115(1):81–8. 263
3. Kelman CD. Phaco-emulsification and aspiration; a new technique of cataract 264
removal: a preliminary report. Am J Ophthalmol. 1967;64:23–35. 265
4. Gimbel H. Divide and conquer nucleofractis phacoemulsification: development and 266
variations. J Cataract Refract Surg. 1991(17):281–91. 267
5. Shepherd J. In situ fracture. 1990;16:436–40. 268
6. Fine I, Maloney W, Dillman O. Crack and flip phacoemulsification technique. J 269
Cataract Refract Surg. 1993;19:797–802. 270
7. Koch P, Katzen L. Stop and chop phacoemulsification. J Cataract Refract Surg. 1994;; 271
20:566–70. 272
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8. Davison JA. Minimal lift-multiple rotation technique for capsular bag 273
phacoemulsification and intraocular lens fixation. J Cataract Refract Surg. 1988 274
Jan;14(1):25–34. 275
9. Steinert RF. Cataract Surgery. Elsevier Health Sciences; 2010. 64 p. 276
10. Faramarzi A, Javadi MA, Karimian F, Jafarinasab MR, Baradaran-Rafii A, Jafari F, et 277
al. Corneal endothelial cell loss during phacoemulsification: bevel-up versus bevel-278
down phaco tip. J Cataract Refract Surg. 2011 Nov;37(11):1971–6. 279
11. Raskin E, Paula JS, Cruz AAV, Coelho RP. Effect of bevel position on the corneal 280
endothelium after phacoemulsification. Arq Bras Oftalmol. 2010 Dec;73(6):508–10. 281
12. Leo T. Chylack Jr, John K. Wolfe, David M. Singer, M. Cristina Leske, Mark A. 282
Bullimore, Ian L. Bailey, et al. The Lens Opacities Classification System III. Arch 283
Ophthalmol. 1993;111:831–6. 284
13. Ventura AC, Wälti R, Böhnke M. Corneal thickness and endothelial density before 285
and after cataract surgery. Br J Ophthalmol. 2001;85(1):18-20. 286
14. Cheng H, Bates AK, Wood L, McPherson K. Positive correlation of corneal thickness 287
and endothelial cell loss. Serial measurements after cataract surgery. Arch 288
Ophthalmol. 1988;106(7):920-2. 289
15. Vijaya L, George R, Arvind H, Ve Ramesh S, Baskaran M, Raju P, et al. Central 290
corneal thickness in adult South Indians: the Chennai Glaucoma Study. 291
Ophthalmology. 2010 Apr;117(4):700–4. 292
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16. Dhand NK, Khatkar M S. Statulator: An online statistical calculator. Sample Size 293
Calculator for Comparing Two Independent Means [Internet]. [cited 2016 Mar 8]. 294
Available from: http://statulator.com/SampleSize/ss2M.html 295
17. Cataract & Refractive Surgery Today Europe - Protecting the Endothelium During 296
Phacoemulsification (April 2015) [Internet]. [cited 2016 Mar 9]. Available from: 297
http://crstodayeurope.com/2015/04/protecting-the-endothelium-during-298
phacoemulsification/ 299
18. Donnenfeld ED, Holland EJ, Solomon KD, Fiore J, Gobbo A, Prince J, et al. A 300
multicenter randomized controlled fellow eye trial of pulse-dosed difluprednate 301
0.05% versus prednisolone acetate 1% in cataract surgery. Am J Ophthalmol. 2011 302
Oct;152(4):609–17.e1. 303
19. Hayashi K, Hayashi H, Nakao F, Hayashi F. Risk factors for corneal endothelial 304
injury during phacoemulsification. J Cataract Refract Surg. 1996 Oct;22(8):1079–84. 305
20. Walkow T, Anders N, Klebe S. Endothelial cell loss after phacoemulsification: 306
relation to preoperative and intraoperative parameters. J Cataract Refract Surg. 2000 307
May;26(5):727–32. 308
21. Hwang HB, Lyu B, Yim HB, Lee NY. Endothelial Cell Loss after 309
Phacoemulsification according to Different Anterior Chamber Depths. J Ophthalmol. 310
2015;2015:210716. 311
312
313
314
315
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Flow diagram for the trial participants
215x279mm (300 x 300 DPI)
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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*
Section/item Item No
Description Line number
Administrative information
Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym 21-23
Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry 50
2b All items from the World Health Organization Trial Registration Data Set 101-04
Protocol version 3 Date and version identifier 101-04
Funding 4 Sources and types of financial, material, and other support 253-4
Roles and
responsibilities
5a Names, affiliations, and roles of protocol contributors 4-10, 250-52
5b Name and contact information for the trial sponsor NA
5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and
interpretation of data; writing of the report; and the decision to submit the report for publication, including
whether they will have ultimate authority over any of these activities
NA
5d 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)
NA
Introduction
Background and
rationale
6a Description of research question and justification for undertaking the trial, including summary of relevant
studies (published and unpublished) examining benefits and harms for each intervention
66-96
6b Explanation for choice of comparators 84-96
Objectives 7 Specific objectives or hypotheses 97-98
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Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group),
allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)
99-100
Methods: Participants, interventions, and outcomes
Study setting 9 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
119-20
Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and
individuals who will perform the interventions (eg, surgeons, psychotherapists)
123-30
Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be
administered
131-77
11b 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)
NA: One time
intervention
11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence
(eg, drug tablet return, laboratory tests)
NA: One time
intervention
11d Relevant concomitant care and interventions that are permitted or prohibited during the trial NA
Outcomes 12 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
192-4
Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits
for participants. A schematic diagram is highly recommended (see Figure)
190, Fig 1
Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including
clinical and statistical assumptions supporting any sample size calculations
200-01
Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size 122
Methods: Assignment of interventions (for controlled trials)
Allocation:
Sequence
generation
16a 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
208-9
Allocation
concealment
mechanism
16b 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
208-9
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Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to
interventions
208
Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome
assessors, data analysts), and how
209-10
17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s
allocated intervention during the trial
NA
Methods: Data collection, management, and analysis
Data collection
methods
18a 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
212-19
18b 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
189
Data management 19 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
NA: single center
trial with relatively
small sample
Statistical methods 20a 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
212-19
20b Methods for any additional analyses (eg, subgroup and adjusted analyses) 212-19
20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any
statistical methods to handle missing data (eg, multiple imputation)
NA
Methods: Monitoring
Data monitoring 21a 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
221-24
21b 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
NA
Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse
events and other unintended effects of trial interventions or trial conduct
226-28
Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent
from investigators and the sponsor
216-19
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Ethics and dissemination
Research ethics
approval
24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval 106-10
Protocol
amendments
25 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)
223-24
Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and
how (see Item 32)
109-10
26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary
studies, if applicable
NA
Confidentiality 27 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
110-13
Declaration of
interests
28 Financial and other competing interests for principal investigators for the overall trial and each study site 253-54
Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that
limit such access for investigators
112-13
Ancillary and post-
trial care
30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial
participation
114-16
Dissemination
policy
31a 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
NA
31b Authorship eligibility guidelines and any intended use of professional writers Author sequence
will be decided
based on the
contributions of all
the investigators
31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code NO
Appendices
Informed consent
materials
32 Model consent form and other related documentation given to participants and authorised surrogates Sup file 1
Biological
specimens
33 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
NA
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*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.
Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons
“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.
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