Esotropia Treatment Study Protocol v 2.0 8-22-05publicfiles.jaeb.org/pedig/protocol/EsotropiaTreatment...Esotropia Treatment Study Protocol v 2.0 8-22-05.doc Protocol Amendment –

Esotropia Treatment Study Protocol v 2.0 8-22-05.doc

1 2 3 4

ESOTROPIA TREATMENT STUDY 1 5 6

ETS1 7 8

An Observational Study of Infantile, Acquired Non-accommodative, and Acquired 9 Partially-accommodative Esotropia 10

11 12

Protocol Chair: Stephen P. Christiansen, M.D. 13 14 15 16

17 18 19 20 21

PROTOCOL 22 23 24 25

Version 2.0 26 27 28

August 22, 2005 29 30

Esotropia Treatment Study Protocol v 2.0 8-22-05.doc Protocol Amendment – Page 1

ESOTROPIA TREATMENT STUDY 1 (ETS1) 31 An Observational Study of Infantile, Acquired Non-accommodative, and Acquired Partially-32

accommodative Esotropia (ETS1) 33 PROTOCOL AMENDMENT #1 - 8-8-05 34

35 This amendment provides for the following protocol changes: 36 37 1. Eliminate SPCT measurements for IET patients and reduce SPCT measurements for AET 38

patients 39 40

Current Protocol 41 The current protocol has the Simultaneous Prism and Cover Test (SPCT) being performed at distance 42 and at near at all study visits for both infantile ET (IET) patients and acquired ET (AET) patients. 43

44 Proposed Changes 45 • Eliminate simultaneous prism and cover test (SPCT) measurements at distance and near for 46

infantile esotropia (IET) patients (sections 2.6, 3.3, 4.4, and 5.2) 47 • Eliminate SPCT measurements at distance and near for acquired esotropia (AET) patients at the 6-48

week and 12-week visits. (sections 2.6, 4.4, and 5.2) 49 50

Rationale for Changes 51 Investigators have mentioned that, in contrast to the typical ATS studies, study visits for ETS1 are 52 quite labor intensive because of the number of alignment measurements required at each visit. As a 53 result, the Steering Committee re-evaluated the purpose of each alignment measurement to identify 54 whether any measurements could be reduced or eliminated without compromising the study’s 55 objectives. The existing alignment measurements for infantile ET (IET) patients and for acquired ET 56 (AET) patients are shown on pages 3 and 4 respectively. The measurement which the Committee felt 57 could be eliminated for some patients and collected less often for others is the Simultaneous Prism 58 and Cover Test (SPCT) for the reasons described below. 59

60 The Simultaneous Prism and Cover Test (SPCT) is difficult to perform with very young patients as 61 has been evidenced by the testability data gathered thus far. An interim review of enrollment data for 62 the study’s 31 IET patients (all of whom are under 1 year of age by definition) revealed that the SPCT 63 at distance had been obtainable in only 4 patients (13%) and the SPCT at near had been obtainable in 64 only 11 patients (35%). Although collecting SPCT measurements in IET patients would be of some 65 clinical interest, they are not used in determining patient eligibility or in the study’s primary analyses. 66

67 In contrast to in IET patients, SPCT data is substantially easier to obtain in AET patients, most of 68 whom are older than one year. In an interim review of enrollment data for the study’s 46 AET 69 patients, SPCT at distance was obtainable in 32 (70%) and SPCT at near was obtainable in 39 (85%). 70 There is also a firm rationale for collecting SPCT data in AET patients. SPCT measurements at 71 distance and near are the first and second measurements, respectively, in a hierarchy which is used in 72 determining patient eligibility. The rationale is that patients who have only a small angle as measured 73 by SPCT would not likely be eventual candidates for surgery and therefore do not represent a group of 74 interest for the present study (note that while this rationale would apply to IET patients as well, the 75 inability to obtain SPCT data in IET patients prevents implementing this consideration in these 76 patients). It was also felt that collecting SPCT measurements during follow up would also be 77 important as they would be expected to impact a decision to operate in any potential future RCT. For 78 these reasons, it was decided that for AET patients, SPCT at distance and at near would be retained at 79 all visits other than the 6-wk and 12-wk pre-operative visits. 80


81 2. Eliminate vertical deviation measurements in IET patients 82 83

Current Protocol 84 The current protocol stipulates that vertical deviation measurements be taken by SPCT at near at the 85 enrollment, 18-wks pre-operative, and 6wks and 6 months postoperative visits for all patients. 86

87 Proposed Change 88 Eliminate measurement of vertical deviation in patients in IET patients and instead collect only 89 whether a vertical deviation is present (sections 2.6, 3.3, 4.4 and 5.2). 90

91 Rationale for Changes 92 The advantage of eliminating the SPCT for IET patients is felt to outweigh the disadvantage of not 93 being able to collect vertical deviation measurements in these patients. Also, while the magnitude of 94 the vertical deviation will not be measured in IET patients, the study will collect data on the presence 95 of a vertical deviation. For AET patients, vertical deviation measurements will continue as SPCT at 96 near is being retained at the visits at which vertical deviation measurements are to be taken. 97

98 99 This amendment also provides for the following protocol clarifications which are unrelated to the 100 protocol changes: 101 102 1. Definitions of constant, variable, and intermittent esotropia have been added to section 1.2 103 104 2. Definitions of infantile esotropia (IET), acquired non-accommodative esotropia (ANAET), and 105

acquired partially accommodative esotropia (APAET) have been clarified in section 1.2 to indicate 106 that each refers to a constant or variable esotropia. 107

108 3. Clarification has been made to section 2.5 to indicate that age of onset of esotropia is considered to be 109

age at the first onset of a constant or variable esotropia. 110 111 4. To eliminate redundancy between chapters, the general considerations which apply to alignment 112

testing throughout the study have been separated from the specification of what alignment testing is to 113 be done certain visits. Specification of what testing is to be done at the specific visit has been moved 114 from the ocular alignment sections 2.6.1, 3.3.1, 4.4.1, 5.2.1 to the examination procedures sections 115 2.6, 3.3, 4.4, and 5.2, respectively. Section 2.6.1 has been changed to general considerations which 116 apply to alignment testing across the study, and section 4.4.1 has been changed to special 117 considerations which apply to alignment testing during follow up. Ocular alignment sections 3.3.1 118 and 5.2.1 have been eliminated. 119

120 5. In sections 2.6.1 and 4.4.1, the word ‘investigator’ has been change to ‘examiner.’ 121 122


ETS1 Alignment Measurements for Infantile ET (IET) Patients 23 Enrollment Spectacle Baseline Follow-Up

Protocol Required Protocol Required Protocol Required

SPCT at distance X X X

SPCT at neara

X

X

X

APCT at distance X X X

Repeat APCT at distance Optional at 6-wk and 12-wkd

APCT at near X X Xc X Xc

Repeat APCT at near Optional at 6-wk and 12-wkd

Krimsky at near Xb Xb Xc Xc Xc Xc

Repeat Krimsky at near

Optional at 6-wk and 12-wkd

Shading indicates testing which would be eliminated by the proposed protocol amendment 24 25 Unless otherwise specified, the measurements which are taken during each testing are horizontal deviation measurements. 26 27 Protocol indicates the measurement is stipulated by the protocol. Required indicates the measurement must be completed. 28 29 aVertical deviation is also measured by SPCT at near at enrollment, IET Baseline Visit, 18-wks pre-op, 6wks post op, and 6-mos post op visits. 30 31 bRequired only if APCT at near is not obtainable at the visit 32 33 cRequired only if Krimksy at near was the only measurement able to be performed at enrollment or IET Spectacle Baseline visit 34 35 dOptional testing performed as part of the test-retest study 36


ETS1 Alignment Measurements for Acquired ET (AET) Patients 37 Enrollment Follow-Up

Protocol

Required

Protocol

Required

SPCT at distance X

X*

SPCT at nearb X

X*

APCT at distance X

X

Repeat APCT at distance For patients currently

in spectacles Optional at 6-wk

and 12-wka

APCT at near X

X

X

X

Repeat APCT at near For patients currently

in spectacles X Optional at 6-wk

and 12-wka 38 Shading indicates testing which would be eliminated by the proposed protocol amendment 39

Unless otherwise specified, the measurements which are taken during each testing are horizontal deviation measurements. 40

Protocol indicates the measurement is stipulated by the protocol. Required indicates the measurement must be completed. 41

*The proposed protocol amendment would eliminate SPCT testing at near and at distance at the 6-wk and 12-wk visits only. Such testing would be 42 retained at all other visits. 43 aOptional testing performed as part of the test-retest study 44 bVertical deviation is also measured by SPCT at near at enrollment, 18-wks pre-op, 6wks post op, and 6-mos post op visits. 45 46 47


CONTACT INFORMATION 148 149 150 151

Coordinating Center 152 153

Jaeb Center for Health Research 154 15310 Amberly Drive, Suite 350 155

Tampa, FL 33647 156 Phone (888) 79PEDIG or (813) 975-8690 157 FAX (888) 69PEDIG OR (813) 975-8761 158

Roy W. Beck, M.D., Ph.D. 159 Director 160

161 162

Protocol Chair 163 164

Stephen P. Christiansen, M.D. 165 Pediatric Ophthalmology and Adult Strabismus 166

Department of Ophthalmology, University of Minnesota 167 MMC 493, 420 Delaware St., SE 168 Minneapolis, MN 55455-0501 169

Phone: (612) 625-4400 170


Table of Contents 171 172

CHAPTER 1: BACKGROUND AND SUMMARY............................................................... 1-1 173 1.1. Rationale for the Study ............................................................................................ 1-1 174 1.2. Definitions................................................................................................................ 1-1 175 1.3. Study Objectives ...................................................................................................... 1-2 176 1.4. Synopsis of the Study............................................................................................... 1-2 177 1.5. Test-retest Ancillary Study ...................................................................................... 1-3 178 1.6. Flow Chart ............................................................................................................... 1-4 179

CHAPTER 2: SCREENING AND ENROLLMENT VISITS................................................. 2-1 180 2.1. Eligibility Assessments and Informed Consent ....................................................... 2-1 181 2.2. Eligibility Criteria .................................................................................................... 2-1 182

2.2.1. Measurement of Ocular Alignment for Study Eligibility ................................ 2-2 183 2.2.2. Measurement of Ocular Alignment for ANAET/APAET Classification ........ 2-2 184

2.3. Definition of Significant Refractive Error ............................................................... 2-2 185 2.4. Timing of Screening and Enrollment....................................................................... 2-3 186

2.4.1 Patients with Infantile ET ................................................................................ 2-3 187 2.4.2 Patients with ANAET and APAET.................................................................. 2-3 188

2.5. Historical Information.............................................................................................. 2-4 189 2.6. Screening/Examination Procedures ......................................................................... 2-4 190

2.6.1 General Considerations for Ocular Alignment Testing ................................... 2-5 191 2.7. Assessment for Presence of Amblyopia .................................................................. 2-5 192 2.8. Prescribing Spectacles (Infantile ET Patients Only)................................................ 2-5 193 2.9. Amblyopia Treatment .............................................................................................. 2-6 194 2.10. Enrollment of Eligible Patients............................................................................ 2-6 195 2.11. Scheduling the Next Visit .................................................................................... 2-6 196

CHAPTER 3: BASELINE VISIT FOR INFANTILE ET PATIENTS PRESCRIBED 197 SPECTACLES......................................................................................................................... 3-1 198

3.1. Overview.................................................................................................................. 3-1 199 3.2. Spectacle Correction ................................................................................................ 3-1 200 3.3. Examination Procedures .......................................................................................... 3-1 201 3.4. Scheduling the Next Visit ........................................................................................ 3-2 202

CHAPTER 4: PRE-OPERATIVE OBSERVATION PHASE ................................................ 4-1 203 4.1. Overview.................................................................................................................. 4-1 204 4.2. Protocol-specified Observation................................................................................ 4-1 205

4.2.1 18-week visit.................................................................................................... 4-1 206 4.3. Additional Pre-operative Observation ..................................................................... 4-1 207 4.4. Examination Procedures .......................................................................................... 4-1 208

4.4.1. Special Considerations for Ocular Alignment Testing During Follow Up...... 4-2 209 4.5. Management of Spectacle Correction...................................................................... 4-2 210 4.6. Treatment ................................................................................................................. 4-2 211

CHAPTER 5: POST-OPERATIVE OBSERVATION PHASE.............................................. 5-1 212 5.1. Visit Schedule .......................................................................................................... 5-1 213 5.2. Examination Procedures .......................................................................................... 5-1 214 5.3. Recording of Surgical Measurements...................................................................... 5-1 215 5.4. Post-surgical Complications .................................................................................... 5-1 216


5.5. Treatment ................................................................................................................. 5-1 217 CHAPTER 6: MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP........................ 6-1 218

6.1. Maintaining Patient Follow Up................................................................................ 6-1 219 6.2. Patient Withdrawals ................................................................................................. 6-1 220 6.3. Treatment of Amblyopia.......................................................................................... 6-1 221 6.4. Risk of Delaying Surgery......................................................................................... 6-1 222 6.5. Risks of Examination Procedures ............................................................................ 6-1 223 6.6. Intercurrent Events................................................................................................... 6-1 224

CHAPTER 7: TEST-RETEST ANCILLARY STUDY .......................................................... 7-1 225 7.1. Overview.................................................................................................................. 7-1 226 7.2. Objectives ................................................................................................................ 7-1 227 7.3. Visit Schedule .......................................................................................................... 7-1 228 7.4. Time Interval Between Alignment Testing and Re-testing ..................................... 7-1 229 7.5. Masking of Examiners ............................................................................................. 7-1 230 7.6. Alignment Measurement.......................................................................................... 7-1 231

CHAPTER 8: STATISTICAL ANALYSIS AND SAMPLE SIZE ESTIMATION............... 8-1 232 8.1. Observational Study................................................................................................. 8-1 233

8.1.1. Data Analysis ........................................................................................................ 8-1 234 8.1.2 Sample Size........................................................................................................... 8-2 235

8.2. Test-Retest Study ..................................................................................................... 8-3 236 8.2.1. Data Analysis ....................................................................................................... 8-3 237 8.2.2. Sample Size.......................................................................................................... 8-3 238

Esotropia Treatment Study Protocol v 2.0 8-22-05.doc 1-1

CHAPTER 1: BACKGROUND AND SUMMARY 239 240

1.1. Rationale for the Study 241 Approximately one third of infants with infantile esotropia (infantile ET) and a similar 242 proportion of children with acquired non-accommodative esotropia (ANAET) will have an 243 increasing angle within the first few months of their initial examination (see separate background 244 document and literature review). In approximately two thirds of patients, the angle of 245 misalignment remains stable and in a small proportion, the angle of esotropia decreases. The 246 changing angle of misalignment in a significant proportion of children with esotropia raises an 247 important question regarding the timing of surgical management of these children: should 248 surgery be undertaken immediately or delayed until the alignment stabilizes? Early surgery may 249 improve sensory outcomes; delayed surgery may improve surgical dosing accuracy and motor 250 outcomes. 251

252 Children with acquired partially accommodative esotropia (APAET) may differ from those with 253 infantile ET and ANAET in that they tend to present at an older age, are more likely to preserve 254 high-grade stereopsis with appropriate treatment, require surgical intervention less frequently, 255 and have more substantial hyperopic refractive errors. Little is known regarding early angle 256 stability in this group of patients following correction of their refractive errors. 257 258 Although there is a need for a randomized trial to address the issue of timing of surgery in 259 infantile ET, APAET, and ANAET, prior to designing such a trial, high-quality preliminary data 260 are needed. We propose a multi-center observational study to 1) determine the duration of 261 misalignment in infantile ET, ANAET, and APAET at study enrollment, 2) to prospectively 262 establish the proportion of patients with angle instability in infantile ET, ANAET, and APAET, 263 and 3) to determine recruitment potential for a randomized trial. These data will be crucial for 264 sample size calculations for the eventual randomized trial, and will help further define the 265 clinical characteristics of these conditions. 266 267 A concurrent and nested ancillary study will be conducted at selected centers to collect test-retest 268 data on alignment measurements for estimating the amount of measurement variability. These 269 test-retest data will be used to define a change in angle alignment that exceeds an amount which 270 could reasonably be due to measurement error, which will be used in evaluating the proportion of 271 patients with angle instability in the current study. 272

273 The study is being coordinated by the Jaeb Center for Health Research in Tampa, Florida and is 274 being funded through a cooperative agreement from the National Eye Institute. The 275 organizational structure of the study group and study policies are detailed in the Pediatric Eye 276 Disease Investigator Group (PEDIG) Bylaws. 277 278 1.2. Definitions 279 Infantile Esotropia (infantile ET) – a constant or variable esodeviation with onset before six 280 months of age 281 282


Acquired Non-Accommodative Esotropia (ANAET) – a constant or variable, non-283 accommodative esodeviation with onset after six months of age, associated with either no 284 significant refractive error (see section 2.3), or an esotropia which decreases by less than 10 285 prism diopters (PD) at distance fixation with correction of refractive error (see section 2.3). 286 287 Acquired Partially Accommodative Esotropia (APAET) – a constant or variable 288 accommodative esodeviation with onset after six months age, associated with an angle which 289 decreases by 10PD or more at distance fixation with correction of refractive error. 290 291 Constant Esotropia – an esotropia which is present all of the time and for which the magnitude 292 of the angle does not appear to vary over the course of an examination 293 294 Variable Esotropia - an esotropia which is present all of the time and for which the magnitude 295 of the angle appears to vary over the course of an examination 296 297 Intermittent Esotropia – an esotropia which is present only some of the time 298 299 Instability of strabismus angle – a change in angle alignment that exceeds an amount which 300 could reasonably be due to measurement error, an amount which will be defined using data from 301 the concurrent nested test-retest ancillary study. 302 303 1.3. Study Objectives 304 o To estimate the duration of misalignment by age at presentation in infantile ET, ANAET and 305

APAET. 306 o To determine the proportion of patients with angle instability in infantile ET, ANAET and 307

APAET by length of follow-up 308 309 1.4. Synopsis of the Study 310 A. Screening and Enrollment 311 Eligible patients with infantile ET will be consented and enrolled at their initial visit. Infantile 312 ET patients who need spectacles (see sections 2.3 and 2.8) will be prescribed spectacles and will 313 return for an Infantile ET Spectacle Baseline Visit 2 weeks later. 314 315 ANAET and APAET patients who present wearing spectacles with appropriate correction (see 316 sections 2.2 and 2.3) for at least 2weeks will be consented and enrolled into the study at that 317 initial visit. 318 319 For ANAET and APAET patients who present not wearing spectacles (see sections 2.2 and 2.3): 320 • Patients who do not need spectacles will be consented and enrolled into the study at that 321

initial visit. 322 • Patients who need spectacles are prescribed appropriate correction if the investigator intends 323

to offer the patient enrollment at a later date. Patients are asked to return after wearing the 324 new spectacles 2-6 weeks, at which time they may be consented and enrolled into the study. 325 The rationale for the delay in enrollment until after a period of spectacle wear for children 326 who have either ANAET or APAET and have significant refractive error or prescription of 327 spectacles for lesser amounts of refractive error, is that we do not propose to study pure 328 accommodative esotropia in this protocol. 329


330 Sample Size: The study will enroll 100 patients for each of the three esotropia types of infantile 331 ET, ANAET, and APAET, for a total of 300 patients. 332 333 B. Follow Up 334 Study follow up consists of the following two phases: 335 • Pre-operative Observation Phase - which includes a protocol-specified 18-week period of 336

observation (with visits every 6 weeks) during which surgery may not be performed, 337 followed by an optional additional period of observation before surgery, the length of which 338 is at investigator discretion. 339

• Post-operative Observation - which consists of a 6-week and a 6-month visit following 340 esotropia surgery. 341

342 C. Examination Procedures 343 At each visit, eye alignment will be measured at distance and at near using the Alternate Prism 344 and Cover Test (APCT). The modified Krimsky test is permitted in children less than 6 months 345 of age if a prism and cover test is not possible. Patients who have ANAET or APAET will also 346 have eye alignment measured by Simultaneous Prism and Cover Test (SPCT) at certain visits. 347 348 All alignment measurements will be taken with appropriate spectacle correction if applicable. 349 350 1.5. Test-retest Ancillary Study 351 At selected sites, a repeat measurement of alignment will be performed at the 6-week and 12-352 week visits as part of a test-retest ancillary study. The repeat measurements will be made by a 353 certified examiner masked to the results of the first examiner. 354 355 The objectives of this ancillary study are as follows: 356 o To determine the interobserver test-retest variability of angle misalignment 357 o To determine the interobserver test-retest variability of a change in angle misalignment 358 o To use these test-retest data to define a change in angle alignment that exceeds an amount 359

which could reasonably be due to measurement error 360

1-4

1.6. Flow Chart 361 362

363 364 365 366 367 368 369 370 371 372 373 374

SURGERY NOT PERFORMED W/I 6 MOS OF 18WK VISIT

Enrollment Visit

• Assessment of patient eligibility • Oculomotor exam • Measurement of ocular alignment • Cycloplegic refraction

6-week visit*

• Measurement of ocular alignment • Oculomotor exam

Prescribe Spectacles

Additional Observation Visits every 6 weeks until investigator ready to operate OR if surgery not

performed within 6 months following 18- week visit

Is the investigator ready to operate?

READY WAIT

6-week Post-operative Visit

• Recording of surgical measurements and post-operative complications


WAIT

ANAET Infantile ET Not Needing Spectacles

18-week visit*

• Measurement of ocular alignment • Oculomotor exam • Cycloplegic refraction

Is the investigator ready to operate?

APAET Infantile ET Needing Spectacles

Infantile ET Spectacle Baseline Visit (within 2 weeks of enrollment)


6-month Post-operative Visit


READY

12-week visit*


*For patients with ANAET or APAET, or for infantile ET patients who do not need spectacles, the 6- 12- and 18 week visits are timed from Enrollment Visit. For infantile ET patients who need spectacles, these visits are timed from the IET Spectacle Baseline Visit.

Discontinue from Study


CHAPTER 2: SCREENING AND ENROLLMENT VISITS 375 376 2.1. Eligibility Assessments and Informed Consent 377 When a patient appears eligible for the study (see section 2.2) following a “standard-care” or 378 preliminary examination, the study will be discussed with the child’s parent(s) or guardian(s). 379 Parent(s) or guardian(s) who express an interest in the study will be given an informed consent 380 form to read. Written informed consent must be obtained from the parent or guardian prior to 381 performing any study-specific procedures that are not part of the patient’s routine care. 382 383 2.2. Eligibility Criteria 384 Age at enrollment: 385 o For infantile ET: less than 12 months old 386 o For ANAET or APAET: 6 months - <5 years old 387

Duration of esotropia less than 6 months by best estimate (photos, parent history, physician 388 records) 389

A constant or variable* esotropia meeting the following criteria: 390 For infantile ET: 391

• Onset before six months of age 392 • Measuring >10 PD by Alternate Prism and Cover Test (APCT) in the primary 393

position at distance fixation on an accommodative target (see section 2.2.1) 394 For ANAET: 395

• Onset after six months of age 396 • Angle decreases less than 10 prism diopters (PD) by Alternate Prism and Cover Test 397

(APCT) in the primary position at distance fixation with correction (see section 2.2.2) 398 • Residual angle measures >10 PD by Simultaneous Prism and Cover Test (SPCT) in 399

the primary position at distance fixation (see section 2.2.1) 400 For APAET: 401

• Onset after six months of age 402 • Angle decreases 10 prism diopters (PD) or more by Alternate Prism and Cover Test 403

(APCT) in the primary position at distance fixation with correction (see section 2.2.2) 404 • Residual angle measures >10 PD by Simultaneous Prism and Cover Test (SPCT) in 405

the primary position at distance fixation (see section 2.2.1) 406 *The deviation can be variable if the minimum angle meets the above criteria, however, a 407 patient whose deviation is intermittent on any measurement is ineligible. 408

Spectacle correction history 409 o For infantile ET: no prior spectacle wear 410 o APAET or ANAET: 411

For patients who have significant refractive error (see section 2.3), full hyperopic 412 correction determined with cycloplegia must have been worn for at least 2 weeks. 413

For patients who do not have significant refractive error (see section 2.3), whether 414 to prescribe spectacles is at investigator discretion, however, if the investigator 415 elects to prescribe spectacles, the full hyperopic correction determined with 416 cycloplegia must have been worn for at least 2 weeks. 417

Parent or legal guardian available for follow-up, has home phone (or access to phone), and 418 willing to be contacted by Jaeb Center staff 419


Gestational age > 34 weeks 420 Birth weight > 1500 grams 421 No atropine use within the last two weeks 422 No history of CNS disease (e.g. IVH, PVL, meningitis, developmental abnormalities of the 423

brain, hydrocephalus, cerebral palsy, hypoxic ischemic encephalopathy) 424 No significant developmental delay in the investigator’s judgment (isolated speech delay 425

excepted) 426 No limitation of abduction consistent with paralytic or restrictive myopathy (minor limitation 427

of abduction due to cross fixation is acceptable) 428 No craniofacial malformation affecting the orbits 429 No prior extraocular muscle surgery or intraocular surgery 430 No structural ocular abnormalities (e.g. media opacity, optic atrophy, optic nerve hypoplasia, 431

retinal detachment) 432 433 2.2.1. Measurement of Ocular Alignment for Study Eligibility 434 For infantile ET patients, eligibility for the study will be determined by the measurement using 435 APCT at distance fixation. If APCT at distance fixation is not able to be completed, then 436 eligibility will be based on APCT at near. If APCT is not able to be completed, eligibility will 437 be based on modified Krimsky measurement at near. 438 439 For ANAET and APAET patients, eligibility for the study will be determined by the 440 measurement using SPCT at distance fixation with spectacle correction, if prescribed. If SPCT 441 at distance fixation is not able to be completed, then eligibility will be based on SPCT at near. If 442 SPCT is not able to be completed, then eligibility will be based on the APCT test at distance. If 443 APCT at distance is not able to be completed, eligibility will be based on APCT at near. It is 444 recognized that SPCT, particularly in smaller angle or moderate esotropia, may not represent the 445 magnitude of the tropia alone, where peripheral fusion may result in a large difference between 446 SPCT and APCT measurements. 447 448 2.2.2. Measurement of Ocular Alignment for ANAET/APAET Classification 449 Classification of enrolled patients with acquired esotropia as having either acquired non-450 accommodative esotropia (ANAET) or acquired partially-accommodative esotropia (APAET) 451 will be made as follows: 452 • Patients not currently wearing spectacles will be classified as ANAET 453 • Patients currently wearing spectacles will be classified by comparing APCT measurements 454

taken with and without correction. Measurements taken at distance will be used unless 455 distance measurements were not possible, in which case at near measurements will be used 456 o If the angle decreases less than 10 prism diopters (PD) with correction, the patient will be 457

classified as ANAET 458 o If the angle decreases 10 prism diopters (PD) or more with correction, the patient will be 459

classified as APAET 460 461 2.3. Definition of Significant Refractive Error 462 A patient is considered to have significant refractive error if the cycloplegic refraction performed 463 at enrollment indicates one or more of the following: 464


• Spherical equivalent in one or both eyes: ≥ +3.00 D for infantile ET and ≥ +2.00 D for 465 ANAET and APAET 466

• Astigmatism in one or both eyes: ≥ +3.50 D for infantile ET and ≥ +2.50 D for ANAET and 467 APAET 468

• Anisometropia ≥ 2.00D in spherical equivalent 469 470 2.4. Timing of Screening and Enrollment 471 2.4.1 Patients with Infantile ET 472 All patients with infantile ET who are eligible for the study will be consented and enrolled at 473 their initial visit because infantile ET patients must have no previous spectacle wear to be 474 eligible for the study and any response to spectacles prescribed at enrollment is of interest as a 475 secondary aim of the study. 476 477 2.4.2 Patients with ANAET and APAET 478 For ANAET and APAET patients who appear eligible for the study, whether these patients may 479 be consented and enrolled at their initial visit or at a subsequent visit depends on whether 480 spectacle correction is currently being worn and/or whether spectacle correction is being 481 prescribed at this visit. 482 483 ANAET and APAET patients with significant refractive error (see section 2.3) must be wearing 484 full correction for at least 2 weeks at the time of enrollment. 485 If at the initial visit the patient has been wearing full correction for at least 2 weeks, the 486

patient is consented and may be enrolled at the initial visit. 487 If at the initial visit the patient has not been wearing full correction for at least 2 weeks, this 488

visit will be considered a pre-study visit. For patients the investigator intends to offer 489 enrollment at a later date: 490 o Spectacles with full correction are prescribed 491 o The patient should return for consenting and enrollment after having worn full correction 492

for at least 2 weeks 493 Note: Once the patient has been wearing spectacles for at least 2 weeks, if the investigator elects 494 to discontinue spectacles prescribed for significant refractive error, the patient is ineligible for 495 the study and should not be enrolled. 496 497 For ANAET and APAET patients with less than significant refractive error (see section 2.3), 498 whether to prescribe spectacles is at investigator discretion. However, if spectacles are 499 prescribed they must be full correction, as partial correction is not permitted. To be eligible for 500 the study, patients must either be wearing full correction for at least 2 weeks, or be wearing no 501 spectacle correction, however: 502

o If spectacles have already been worn at least 2 weeks, the patient may be consented and 503 enrolled at the initial visit 504

o If at the initial visit the investigator elects to prescribe either spectacles for the first time 505 or a change in spectacles, this visit will be considered a pre-study visit. For patients the 506 investigator intends to offer enrollment at a later date: 507


Spectacles with full correction are prescribed 508 The patient should return for consenting and enrollment after having worn the 509

new spectacles correction for 2-6 weeks 510 Note: Once the patient has been wearing spectacles for at least 2 weeks, if the investigator elects 511 to discontinue spectacles prescribed for less than significant refractive error, the patient is 512 eligible for the study provided the investigator agrees not to re-start spectacles for at least the 18-513 week protocol-specified observation period. 514 515 2.5. Historical Information 516 Information will be collected on the age of the patient at onset of the esotropia. The information 517 will be based on discussion with the parent /guardian and will be corroborated with photographs 518 and/or primary care physician’s notes if available. In addition, the parent or guardian will be 519 asked to complete a brief questionnaire to help better define the timing of onset of esotropia. 520 The investigator will be asked to consider all of the available information to estimate the age at 521 first onset of a constant or variable esotropia. The investigator’s best estimate will be used for 522 calculating the duration of misalignment at enrollment. 523 524 Other historical information to be collected will include the following: date of birth, gender, 525 ethnicity, prior amblyopia therapy (e.g., patching, pharmacologic, filters), spectacle correction, 526 history of allergy/intolerance to cycloplegic eye drops, and family history of strabismus. 527 528 For ANAET and APAET patients currently wearing spectacles, information will be collected on 529 the length of time the current spectacles have been worn. Also, if the current spectacles were 530 prescribed by the investigator, retrospective data on the patient’s alignment will be collected on 531 the patient’s angle measurement without correction (using APCT at distance and near) at the 532 time the current spectacles were initiated. 533 534 2.6. Screening/Examination Procedures 535 The examination procedures to be completed at enrollment include: 536 • Binocular alignment testing as follows, performed in accordance with the general 537

considerations for alignment testing as described in section 2.6.1: 538 For IET patients: 539

o APCT at distance and at near without correction 540 o In patients younger than 6 months old, a modified Krimsky test at near is 541

acceptable if APCT is not possible. 542 For ANAET and APAET patients: 543

SPCT at distance and at near, performed with correction if the patient is currently 544 wearing spectacles. SPCT at near will include measurement of any vertical 545 deviation. 546

APCT at distance and at near, performed with correction if the patient is currently 547 wearing spectacles 548

For patients currently wearing spectacles only: repeat APCT at distance and near 549 without correction 550

• Oculomotor examination including the following: 551 o Version testing with attention to vertical incomitance such as ‘A,’ ‘V,’ ‘Y’, 552

‘lambda’, or ‘X’ patterns 553


o Assessment for presence of inferior oblique overaction (IOOA), vertical 554 deviation, dissociated vertical deviation (DVD), and nystagmus 555

• Cycloplegic retinoscopic refraction (if not performed within prior 2 months) 556 o 1% cyclopentolate is used, however 0.5% cyclopentolate may be used in patients 557

< 6 months old, if desired 558 • Ocular exam including dilated funduscopic examination (if not performed within prior 2 559

months) 560 • Assessment for presence of amblyopia (see section 2.7) 561

562 2.6.1 General Considerations for Ocular Alignment Testing 563 Both SPCT and APCT methods of testing binocular alignment are done using an accommodative 564 target at distance (if possible) and at near fixation. Measurements are recorded to the nearest 565 prism step (as opposed to rounded either consistently down or up). 566 567 Testing is completed in the following order: 568 • If SPCT testing is required, it should be performed prior to APCT testing. 569 • For a given testing method, measurement should be taken first at distance and then at near. 570 • If testing is required both with and without correction, testing is completed with correction 571

first and then completed without correction 572 573 If during the course of taking a measurement, the examiner notices that the angle is variable, the 574 type of esotropia is recorded as variable and the maximum angle observed is recorded as the 575 measurement. 576 577 If a cycloplegic refraction is performed at this visit, all alignment testing must be done prior to 578 cycloplegia. 579 580 2.7. Assessment for Presence of Amblyopia 581 Presence of amblyopia is assessed by optotype visual acuity in patients in whom optotype testing 582 is possible. Amblyopia will be considered present if two lines or more difference exists in visual 583 acuity between the eyes. 584 585 In patients in whom optotype testing is not possible, presence of amblyopia is assessed by 586 fixation behavior. Amblyopia will be considered present if the patient is unable to maintain 587 fixation with the non-preferred eye through a blink. 588 589 2.8. Prescribing Spectacles (Infantile ET Patients Only) 590 For infantile ET patients with significant refractive error (see section 2.3): 591 o Spectacles with the full cycloplegic refraction are prescribed 592 o The patient should return in 2 weeks for the Infantile ET Spectacle Baseline Visit for 593

measurement of alignment with spectacles 594 The patient should begin wearing the spectacles as soon as the spectacles are able to 595

be obtained. 596 597


For infantile ET patients with less than significant refractive error (see section 2.3), whether to 598 prescribe spectacles is at investigator discretion, however, if the investigator elects to prescribe 599 spectacles, the full hyperopic correction must be prescribed. 600 601 2.9. Amblyopia Treatment 602 If amblyopia is identified, patching treatment may be initiated at enrollment or at any time 603 amblyopia is identified during the study. The timing and duration of occlusion will be left to 604 investigator discretion. Neither atropine nor any other amblyopia treatment other than patching 605 may be used. 606 607 2.10. Enrollment of Eligible Patients 608 The study will enroll 100 patients for each of the three esotropia-type groups (infantile ET, 609 ANAET, and APAET) for a total of 300 patients. 610 611 A patient can be enrolled either by entering the Enrollment Form on the PEDIG website or by 612 faxing the form to the Jaeb Center if internet access is down. Each enrolled patient will be 613 assigned a unique identifier number. 614 615 2.11. Scheduling the Next Visit 616 Infantile ET patients prescribed spectacles at the enrollment visit should return in 2 weeks for an 617 Infantile ET Spectacle Baseline Visit to obtain baseline measurements of alignment with 618 spectacles. 619 620 All other patients are scheduled to return for their first follow-up visit in 6 (+1) weeks. 621


CHAPTER 3: BASELINE VISIT FOR INFANTILE ET PATIENTS PRESCRIBED 622 SPECTACLES 623

624 3.1. Overview 625 Infantile ET patients who were prescribed spectacles at enrollment will return for the Infantile 626 ET Spectacle Baseline Visit within 2 weeks. At this visit, ocular alignment will be tested with 627 correction. Alignment may be retested without spectacle correction at investigator discretion. 628 However, measurements without correction will be required if spectacles are discontinued at this 629 visit. 630 631 3.2. Spectacle Correction 632 At this visit, the spectacle prescription is verified with a lensometer. Sphere and cylinder power 633 must be within 0.25 D and cylinder axis within 10 degrees of the prescribed correction. 634 • If these criteria are not met, the spectacles must be re-made and the patient will return within 635

2 weeks for the Infantile ET Spectacle Baseline Visit. 636 637 If the spectacles are not brought to the visit, the patient should return within 2 weeks with the 638 spectacles to complete the Infantile ET Spectacle Baseline Visit. If the spectacles are not 639 brought when the patient returns for the 2nd attempt, spectacles are discontinued and alignment is 640 measured without correction at that visit and at the 6, 12, and 18 week follow up visits. 641 642 The amount of time the patient has been wearing the prescribed spectacle correction will be 643 recorded on the exam form. 644 645 If the patient’s angle of deviation on either APCT at distance or near measured wearing 646 spectacles decreased by more than 5 PD from the respective measurement taken without 647 correction at the enrollment visit, the spectacles must be continued. If the patient’s angle of 648 deviation on both APCT at distance or near measured wearing spectacles did not decrease by 649 more than 5PD from the enrollment visit, the decision on whether to continue spectacle wear is 650 at investigator discretion. 651 652 3.3. Examination Procedures 653 The examination procedures to be completed at the Infantile ET Spectacle Baseline Visit are as 654 follows: 655 Binocular alignment testing as follows, performed in accordance with the general 656

considerations for alignment testing as described in section 2.6.1: 657 o APCT at distance and at near with correction will be completed for all patients 658 o If APCT testing was not possible at the Enrollment Visit: modified Krimsky test at near 659

with correction 660 o If the modified Krimsky test is required, it should be completed before the APCT so 661

that the APCT results do not influence the examiner’s assessment of the modified 662 Krimsky. 663

All alignment testing should be repeated without correction if the investigator plans to 664 discontinue spectacles at the visit (see section 3.2). 665

Oculomotor examination including the following: 666


o Version testing with attention to vertical incomitance such as ‘A,’ ‘V,’ ‘Y’, ‘lambda’, or 667 ‘X’ patterns 668

o Assessment for presence of inferior oblique overaction (IOOA), vertical deviation, 669 dissociated vertical deviation (DVD), and nystagmus 670

Assessment for presence of amblyopia (see section 2.7) 671 • A cycloplegic refraction is not required but may be performed at investigator discretion. 672

• The investigator may perform a dry retinoscopy at any visit to help determine whether a 673 cycloplegic refraction should be performed. 674

• If a cycloplegic refraction is performed and the investigator elects to change the 675 spectacles, the patient should return for the Infantile ET Spectacle Baseline Visit in 2 676 weeks. 677

678 3.4. Scheduling the Next Visit 679 Patients are scheduled to return for a follow up visit in 6 (+1) weeks. 680 681


CHAPTER 4: PRE-OPERATIVE OBSERVATION PHASE 682 683 4.1. Overview 684 The Pre-operative Observation Phase includes consists of two parts: 685 o A protocol-specified 18-week period of observation during which esotropia surgery may not 686

be performed 687 o An optional additional period of observation before esotropia surgery, the length of which is 688

at investigator discretion. 689 690 4.2. Protocol-specified Observation 691 The 18-week protocol-specified observation period consists of follow-up visits at 6, 12, and 18 692 weeks. All visit windows are +1 week. 693 o For infantile ET patients prescribed spectacles at enrollment, follow up visits are timed from 694

the Infantile ET Spectacle Baseline Visit 695 o For ANAET patients, APAET patients, and infantile ET patients not prescribed spectacles at 696

enrollment, follow up visits are timed from the Enrollment Visit. 697 698 Every effort is made to schedule protocol-specified examinations near the target date. 699 • If a patient was early or late for the 6-week visit, the 12-week visit is scheduled so that the 700

visits are 6 weeks apart (i.e. if a patient has the 6 week visit at end of its visit window, 701 schedule the 12 week visit for the end of its visit window). 702

• Regardless of the timing of the 6- and 12-week visits, the 18-week visit is completed as close 703 to the 18-week target date as possible. 704

705 Additional visits within the 18-week period are at the investigator’s discretion, although data will 706 not be collected at these visits. 707 708 4.2.1 18-week visit 709 At the 18-week visit, the investigator may elect to do either of the following: 710

• Schedule surgery OR 711 • Schedule the patient to return for another pre-operative visit in 6 weeks (i.e. 24 weeks) 712

713 4.3. Additional Pre-operative Observation 714 Additional pre-operative observation pertains only to patients for whom at the 18-week visit the 715 investigator has decided to continue observing the patient before surgery. Such patients will 716 have visits every 6 weeks until the investigator decides to schedule surgery, with additional visits 717 at investigator discretion. 718 719 If after 6 months of additional pre-operative observation the patient has not had surgery, the 720 patient will have a final visit and be discontinued from the study. 721 722 4.4. Examination Procedures 723 • Binocular alignment testing as follows, performed in accordance with the general 724 considerations for alignment testing as described in section 2.6.1: 725

APCT at distance and at near will be completed for all patients 726


The following additional testing should be performed as applicable: 727 o At visits occurring at 18 wks or later for patients with ANAET or APAET only: 728

SPCT at distance and at near will be performed prior to APCT testing. At the 18-729 week visit, SPCT at near will include measurement of any vertical deviation. 730

o If APCT testing was not able to be completed at the baseline visit(i.e. the 731 Enrollment Visit for patients not prescribed spectacles and the Infantile ET 732 Spectacle Baseline Visit for patients prescribed spectacles): modified Krimsky 733 test should be performed before APCT 734

o At the 6-week and 12-week visits, if another certified examiner is available: retest 735 of APCT and/or modified Krimsky by another examiner (see chapter 7) 736

If the patient is wearing spectacles, alignment is measured with the spectacles. 737 738 Oculomotor examination including the following: 739

o Version testing with attention to vertical incomitance such as ‘A,’ ‘V,’ ‘Y’, ‘lambda’, 740 or ‘X’ patterns 741

o Assessment for presence of inferior oblique overaction (IOOA), vertical deviation, 742 dissociated vertical deviation (DVD), and nystagmus 743

• Assessment for presence of amblyopia (see section 2.7) 744 • At the 18-week visit, a cycloplegic refraction will be performed to evaluate whether refractive 745

error has changed during follow up 746 o In the event that the investigator wishes to perform a cycloplegic refraction at a 747

visit other than the 18 week visit, all alignment testing (and retesting if the visit is 748 at 6 or 12 weeks), must be performed prior to cycloplegia. 749

750 4.4.1. Special Considerations for Ocular Alignment Testing During Follow Up 751 All alignment measurements are made without review of prior alignment measurements. 752 Although the potential for remembering a patient’s alignment measurements from visit to visit is 753 unavoidable, prior to performing the alignment measurements for a given visit, the examiner 754 should not look up previous alignment measurements in the patient’s chart. 755 756 4.5. Management of Spectacle Correction 757 During the 18-week protocol-specified observation period, spectacles may not be changed, nor 758 can spectacles be prescribed for the first time. 759 760 During the additional pre-operative observation period, spectacles may be changed or prescribed 761 for the first time at investigator discretion. 762 763 4.6. Treatment 764 Surgery may not be performed during the protocol-specified 18-week pre-operative observation 765 period, but may be performed at any time thereafter. Surgery will be performed according to the 766 investigator’s usual practice. 767 768


CHAPTER 5: POST-OPERATIVE OBSERVATION PHASE 769 770 5.1. Visit Schedule 771 The Post-operative Observation Phase includes consists of visits at 6 (+1) weeks and 6 months 772 (between 5 and 8 months), timed from the date of surgery. Additional visits are at the 773 investigator’s discretion. 774 775 5.2. Examination Procedures 776 o Binocular alignment testing as follows, performed in accordance with the general 777

considerations for alignment testing as described in section 2.6.1: 778 o APCT at distance and at near will be completed for all patients 779 o For ANAET and APAET patients: SPCT at distance and at near should be performed 780

before APCT testing 781 If the patient is wearing spectacles, alignment is measured with the spectacles 782

o Oculomotor examination including the following: 783 Version testing with attention to vertical incomitance such as ‘A,’ ‘V,’ ‘Y’, 784

‘lambda’, or ‘X’ patterns 785 o Assessment for presence of inferior oblique overaction (IOOA), vertical 786

deviation, dissociated vertical deviation (DVD), and nystagmus 787 o Assessment for presence of amblyopia (see section 2.7) 788 789 5.3. Recording of Surgical Measurements 790 At the 6-week post-operative visit, the type of surgery performed and the amount of surgery will 791 be recorded on the exam form. Each muscle operated upon will be recorded, with the amount on 792 recession, resection and/or transposition. 793 794 5.4. Post-surgical Complications 795 At the visit 6 weeks after surgery, any patient complications that are directly attributable to 796 surgery will be recorded on the exam form. 797 798 5.5. Treatment 799 If further surgical procedures are performed during the 6 months of post-operative follow-up, the 800 types and amounts will be recorded on the 6-month post-surgical follow-up form.801


802

CHAPTER 6: MISCELLANEOUS CONSIDERATIONS IN FOLLOW-UP 803 804 6.1. Maintaining Patient Follow Up 805 The Jaeb Center may contact the parents or guardian of each patient if needed to help coordinate 806 scheduling of examinations. Parents or guardians may receive updates and information about the 807 study in the mail and a study logo item may be sent once a year. Permission for such contacts 808 will be included in the Informed Consent Form. 809 810 6.2. Patient Withdrawals 811 A patient (and in this case the parents or guardian) may withdraw from the trial at any time. If 812 the parents or guardian indicate that they want to withdraw the child from the study, the 813 investigator personally should attempt to speak with them to determine the reason. If their 814 interest is in transferring the child’s care to another eye care provider, every effort should be 815 made to comply with this and to attempt to keep the patient in the study under the new provider’s 816 care. 817 818 6.3. Treatment of Amblyopia 819 For patients who have amblyopia upon entering the study or who develop ambylopia at any time 820 during the study, patching treatment may be initiated or continued at investigator discretion. The 821 timing and duration of occlusion is also at investigator discretion. Neither atropine nor any other 822 amblyopia treatment other than patching may be used. 823 824 6.4. Risk of Delaying Surgery 825 The protocol stipulation that surgery may not be performed within the first 18 weeks of the study 826 is comparable to the common practice of many clinicians to monitor a patient’s alignment over 827 several visits to determine whether the angle is stable before operating. Although delaying 828 surgery may potentially compromise stereoacuity outcome, this risk must be weighed against the 829 possibility of increased need for re-operation in patients who undergo surgery before the angle of 830 alignment has stabilized. 831 832 6.5. Risks of Examination Procedures 833 The procedures in this study are part of daily ophthalmologic practice in the United States and 834 pose no known risks. As part of a routine usual-care exam, the patient may receive 835 cycloplegic/dilating eye drops. 836 837 6.6. Intercurrent Events 838 Eye injuries or the development of an eye problem that might affect vision will be reported on 839 the Follow-up Examination Form. Likewise, the development of a serious medical problem that 840 might affect the patient’s study participation will be recorded.841


842

CHAPTER 7: TEST-RETEST ANCILLARY STUDY 843 844 7.1. Overview 845 The test-retest study will be conducted at clinical centers in which a second certified examiner is 846 available to repeat certain alignment measurements. The study data will consist of initial 847 alignment measurements taken at the 6-week and 12-week visits as part of the main study and 848 repeat measurements taken at these visits 15 minutes to 1 hour later by a second examiner 849 masked to the results of the first examiner. 850 851 7.2. Objectives 852 • To determine the interobserver test-retest variability of angle misalignment 853 • To determine the interobserver test-retest variability of a change in angle misalignment 854 • To use these test-retest data to define a change in angle alignment that exceeds an amount 855

which could reasonably be due to measurement error 856 857 7.3. Visit Schedule 858 The test-retest study will be conducted at the 6-week and 12-week visits for the main study. The 859 rationale for not using the Enrollment or Infantile ET Spectacle Baseline Visits was that the 860 potential for cycloplegia at these visits would complicate having repeat measurements taken. 861 862 7.4. Time Interval Between Alignment Testing and Re-testing 863 The retesting of alignment by the second examiner should take place between 15 minutes and 864 one hour after completion of the alignment measurements by the first examiner. This interval 865 should allow adequate time for the patient to re-establish any possible binocular fusion after 866 testing by the first examiner, while limiting the effect of temporal patient factors on alignment 867 measurements. 868 869 7.5. Masking of Examiners 870 The first and second examiners are masked to each other’s measurements at the given visit, and 871 to their own measurements from the previous visit (i.e. neither examiner should review the 872 patient’s alignment history prior to obtaining measurements.) Each examiner will be asked to 873 record on the exam form whether he/she can recall any previous measurements for the patient. 874 875 7.6. Alignment Measurement 876 The alignment measurements to be repeated by the second examiner are the APCT at distance 877 and near, unless APCT testing could not be completed at enrollment, in which case a modified 878 Krimsky measurement is repeated in addition to the APCT. 879 • The modified Krimsky test is performed first so that the APCT results do not influence the 880

examiner’s assessment of the modified Krimsky. 881 882 Alignment measurements will be made with correction if the patient is wearing spectacles. 883 884 In the rare event that the investigator wishes to perform a cycloplegic refraction at the visit, the 885 repeat measurements by the second examiner must be performed prior to cycloplegia. 886 887


CHAPTER 8: STATISTICAL ANALYSIS AND SAMPLE SIZE ESTIMATION 888 889 8.1. Observational Study 890 8.1.1. Data Analysis 891 All analyses will be conducted separately according to esotropia type (i.e. infantile ET, ANAET, 892 APAET). 893 894 Throughout the observation period, the measurement to be used for analysis will be one taken by 895 the first examiner (i.e. the investigator). 896 897 Primary Analyses 898 The study will enroll 100 patients for each of the three esotropia types of infantile ET, ANAET, 899 and APAET, for a total of 300 patients. However, the primary analyses will include only 900 patients whose initial angle is between 20PD and 50PD for infantile ET patients or between 901 15PD and 50PD for ANAET and APAET patients, AND who have not had amblyopia during the 902 18-week protocol-specified follow up period. 903 904 The angle measurement used as the initial angle for the purpose of inclusion in the primary 905 analysis is as follows: 906 • For infantile ET patients not prescribed spectacles at enrollment: measurement taken at 907

Enrollment Visit by APCT at near (if performed), otherwise by modified Krimsky at near 908 • For infantile ET patients prescribed spectacles at enrollment: measurement taken at Infantile 909

ET Spectacle Baseline Visit by APCT at near (if possible), otherwise by modified Krimsky at 910 near 911

The measurement taken with correction will be used unless the patient is 912 discontinuing spectacles (see section 3.2), in which case the measurement taken 913 without correction will be used. 914

• For ANAET and APAET patients: measurement taken at Enrollment Visit by APCT at near 915 916 Patients will be considered to have amblyopia and will be excluded from the primary analysis if 917 at any visit throughout the 18-week protocol-specified observation period amblyopia is either 918 detected or amblyopia treatment is either received or prescribed. 919 920 The primary analyses for the observational study are: 921 • To describe the distribution of duration of angle misalignment at enrollment, both overall and 922

according to age. 923 • To determine the proportion of patients whose angle is unstable over 18 weeks of follow up 924 925 For describing the distribution of duration of angle misalignment at enrollment, the investigator’s 926 best estimate the age of onset of esotropia will be used for analysis. 927 928 For determining the proportion of patients whose angle is unstable over 18 weeks of follow up: 929 • Change over 18 weeks will be calculated as the difference between the following 930

measurements taken with correction (if the patient is wearing spectacles): the 18-week 931 measurement and either the Infantile ET Spectacle Baseline Visit measurement for infantile 932


ET patients prescribed spectacles at enrollment or the Enrollment Visit measurement for all 933 other patients. 934

o Measurements will be taken using APCT at near. If the APCT at near cannot be 935 obtained, the Krimsky measurement will be used. 936

o Data from measurements taken using cover testing and data from measurements 937 taken using the modified Krimsky method will be analyzed separately. 938

• Angle instability will be considered to be present if the change in angle alignment is greater 939 than that which could reasonably be due to measurement error. 940

o Measurement error will be defined using data from the test-retest study on the 941 95% confidence interval for a change in measurements. 942

• A proportion of patients whose angle is unstable will be estimated and a 95% confidence 943 interval calculated for this proportion. 944

945 Secondary Analyses 946 Secondary analyses related to angle instability will include: 947 • Evaluating angle instability by length of follow up (i.e. evaluating change over 6 weeks and 948

change over 12 weeks 949 • Evaluating whether instability over a given period is related to previous instability 950 • To determine if angle instability is related to patient characteristics at enrollment such as 951

significant hyperopia, amblyopia, etc. 952 953 Additional secondary analyses will include: 954 • Estimating the rate of development of inferior oblique overaction (IOOA), vertical deviation, 955

and dissociated vertical deviation (DVD) 956 • Evaluating post-operative alignment outcomes at 6 weeks and 6 months. 957 • Determining the response of patients with infantile ET to spectacles 958 959 8.1.2 Sample Size 960 The sample size for the primary analysis of 50 patients per esotropia-type group (infantile ET, 961 ANAET, APAET) was determined based on the width of the 95% confidence interval (CI) for 962 the proportion of patients with angle instability within each group. Because the existing 963 literature suggests that the proportion of patients with angle instability is about one-third for 964 infantile ET and for ANAET, 95% confidence interval half-widths were calculated for 965 proportion of angle instability estimates ranging from 10% to 50%. Table 1 (see next page) 966 displays the expected 95% CIs for sample sizes between 25 and 200 patients per group. 967 968


Table 1. Expected 95% Confidence Interval for Estimate of Proportion with Angle 969 Instability 970 Proportion with Angle Instability Sample Size (per group)

10%

20%

30%

40%

50%

25 0% - 22% 4% - 36% 12% – 48% 21% – 59% 30 – 80%

50 2% - 18% 9% - 31% 17% – 43% 26% - 54% 36% - 64%

100 4% - 16% 12% - 28% 21% – 39% 30% - 50% 40% – 50%

150 5% - 15% 14% - 26% 24% - 36% 32% - 48% 42% - 57%

200 6% - 14% 15% - 26% 26% – 36% 33% - 47% 43% – 57% 971 Based on these data, a sample size of 50 patients was selected for patients in each of the three 972 esotropia-type groups to be included in the primary analysis who have an initial angle within 973 range of interest (see section 8.1.1.) and who are not treated for amblyopia during the study. If 974 we observe the expected 30% of patients with angle instability, this sample size of 50 per group 975 will provide a 95% CI ranging from 17% to 43%. 976 977 978 8.2. Test-Retest Study 979 8.2.1. Data Analysis 980 For each type of esotropia, test-retest differences will be calculated from the alignment data from 981 two examiners each taking measurements at the same visits. Pairs of test-retest data from both 982 the 6-week and the 12-week visits will be used to estimate the test-retest reliability of angle 983 measurements using a generalized linear model to accounting for the non-independence of data. 984 95% confidence intervals will be estimated for an angle measurement and for a change in angle 985 measurements. 986 987 Secondary analyses will evaluate within each type of esotropia whether test-rest reliability is 988 related to patient age, presence of amblyopia, the size of the esodeviation, or whether the 989 character of the esodeviation is constant or variable. 990 991 8.2.2. Sample Size 992 There are no applicable pilot data available on the test-retest reliability of angle measurements on 993 which to base a sample size estimate. We expect the test-retest study to include all patients in 994 the observational study except for the few patients enrolled at sites that will not have a second 995 examiner available. 996 997 998

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