bmj openfor peer review only 5 89 down) [9]. however, faramarzi a et al [10] hypothesize that in the...

For peer review only

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

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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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


*Corresponding author: [email protected] 10

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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


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

1. Linebarger EJ, Hardten DR, Shah GK, Lindstrom RL. Phacoemulsification and 254

modern cataract surgery. Surv Ophthalmol. 1999 Oct;44(2):123–47. 255

2. Kim EK, Cristol SM, Geroski DH, McCarey BE, Edelhauser HF. COrneal endothelial 256

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

4. Gimbel H. Divide and conquer nucleofractis phacoemulsification: development and 261

variations. J Cataract Refract Surg. 1991(17):281–91. 262

5. Shepherd J. In situ fracture. 1990;16:436–40. 263

6. Fine I, Maloney W, Dillman O. Crack and flip phacoemulsification technique. J 264

Cataract Refract Surg. 1993;19:797–802. 265

7. Koch P, Katzen L. Stop and chop phacoemulsification. J Cataract Refract Surg. 1994;; 266

20:566–70. 267

8. Davison JA. Minimal lift-multiple rotation technique for capsular bag 268

phacoemulsification and intraocular lens fixation. J Cataract Refract Surg. 1988 269

Jan;14(1):25–34. 270

9. Steinert RF. Cataract Surgery. Elsevier Health Sciences; 2010. 64 p. 271

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10. Faramarzi A, Javadi MA, Karimian F, Jafarinasab MR, Baradaran-Rafii A, Jafari F, et 272

al. Corneal endothelial cell loss during phacoemulsification: bevel-up versus bevel-273

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

12. Leo T. Chylack Jr, John K. Wolfe, David M. Singer, M. Cristina Leske, Mark A. 277

Bullimore, Ian L. Bailey, et al. The Lens Opacities Classification System III. Arch 278

Ophthalmol. 1993;111:831–6. 279

13. Ventura AC, Wälti R, Böhnke M. Corneal thickness and endothelial density before 280

and after cataract surgery. Br J Ophthalmol. 2001;85(1):18-20. 281

14. Cheng H, Bates AK, Wood L, McPherson K. Positive correlation of corneal thickness 282

and endothelial cell loss. Serial measurements after cataract surgery. Arch 283

Ophthalmol. 1988;106(7):920-2. 284

15. Vijaya L, George R, Arvind H, Ve Ramesh S, Baskaran M, Raju P, et al. Central 285

corneal thickness in adult South Indians: the Chennai Glaucoma Study. 286

Ophthalmology. 2010 Apr;117(4):700–4. 287

16. Dhand NK, Khatkar M S. Statulator: An online statistical calculator. Sample Size 288

Calculator for Comparing Two Independent Means [Internet]. [cited 2016 Mar 8]. 289

Available from: http://statulator.com/SampleSize/ss2M.html 290

17. Cataract & Refractive Surgery Today Europe - Protecting the Endothelium During 291

Phacoemulsification (April 2015) [Internet]. [cited 2016 Mar 9]. Available from: 292

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http://crstodayeurope.com/2015/04/protecting-the-endothelium-during-293

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



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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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


BMJ Open on F

ebruary 23, 2020 by guest. Protected by copyright.

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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


2Department of Community Medicine, Yenepoya Medical College, Yenepoya University, 8


*Corresponding author: [email protected] 10

11

12

13

14

15

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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


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


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

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Phacoemulsification (April 2015) [Internet]. [cited 2016 Mar 9]. Available from: 297

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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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bmj openfor peer review only 5 89 down) [9]. however, faramarzi a et al [10] hypothesize that in the...

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