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A11 Residual protocol v4.0_ 4-30-08.doc

AMBLYOPIA TREATMENT STUDY

(A11)

A Randomized Trial to Evaluate Combined Patching-Atropine

for Residual Amblyopia

PROTOCOL

Version 4.0

April 30, 2008


Contact Information

Coordinating Center

Raymond T. Kraker, M.S.P.H. (Assistant Director) Jaeb Center for Health Research 15310 Amberly Drive, Suite 350

Tampa, FL 33647 Phone (888) 79PEDIG or (813) 975-8690

Fax (888) 69PEDIG or (813) 975-8761

Protocol Chair David K. Wallace, M.D., M.P.H.

Duke University Eye Center Durham, NC

Phone: (919) 684-4584


CHAPTER 1: BACKGROUND AND SUMMARY ................................................................................................... 1-1 1 1.1 Objective ........................................................................................................................... 1-1 2 1.2 Rationale for the Study ..................................................................................................... 1-1 3 1.3 Synopsis of Study Design ................................................................................................. 1-1 4 1.4 Study Summary Flow Chart.............................................................................................. 1-3 5

CHAPTER 2: PATIENT ENROLLMENT (BASELINE VISIT) ............................................................................. 2-1 6 2.1 Eligibility Assessment and Informed Consent .................................................................. 2-1 7 2.2 Eligibility and Exclusion Criteria ..................................................................................... 2-1 8 2.3 Examination Procedures ................................................................................................... 2-2 9

2.3.1 Historical Information ............................................................................................... 2-2 10 2.3.2 Clinical Testing ......................................................................................................... 2-3 11

2.4 Randomization of Eligible Patients .................................................................................. 2-3 12 2.4.1 Delay in Randomization ........................................................................................... 2-3 13 2.4.2 Reading Glasses ........................................................................................................ 2-4 14

CHAPTER 3: TREATMENT AND FOLLOW UP .................................................................................................... 3-1 15 3.1 Treatment Groups ............................................................................................................. 3-1 16

3.1.1 Compliance ............................................................................................................... 3-1 17 3.2 Follow-up Examinations ................................................................................................... 3-1 18

3.2.1 Telephone Call .......................................................................................................... 3-2 19 3.2.2 Letter Reminder ........................................................................................................ 3-2 20 3.2.3 Primary Outcome Visit ............................................................................................. 3-2 21 3.2.4 Follow-Up Visits after the Primary Outcome ........................................................... 3-3 22

CHAPTER 4: MISCELLANEOUS CONSIDERATIONS ........................................................................................ 4-1 23 4.1 Management of Optical Correction .................................................................................. 4-1 24 4.2 Management of Strabismus............................................................................................... 4-1 25 4.3 Worsening of Visual Acuity in the Amblyopic Eye ......................................................... 4-1 26 4.4 Patient Withdrawals .......................................................................................................... 4-1 27 4.5 Risks .................................................................................................................................. 4-1 28 4.6 Risks of Examination Procedures ..................................................................................... 4-1 29 4.7 Adverse Events/Risks ....................................................................................................... 4-1 30

4.7.1 Side Effects of Treatment ......................................................................................... 4-1 31 4.7.2 Reverse Amblyopia ................................................................................................... 4-2 32 4.7.3 Development of Strabismus ...................................................................................... 4-3 33

4.8 Reporting of Adverse Events ............................................................................................ 4-3 34 4.9 Patient Payments ............................................................................................................... 4-3 35 4.10 Discontinuation of Study .................................................................................................. 4-3 36 4.11 Contacts by the Jaeb Center for Health Research ............................................................. 4-3 37

CHAPTER 5: SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS................................................. 5-1 38 5.1 Sample Size Estimation .................................................................................................... 5-1 39 5.2 Primary Analysis ............................................................................................................... 5-1 40 5.3 Secondary Analyses .......................................................................................................... 5-1 41 5.4 Safety Analysis ................................................................................................................. 5-2 42

CHAPTER 6: REFERENCES ...................................................................................................................................... 6-1 43 44

A11 Residual protocol v4.0_ 4-30-08.doc 1-1

45 Chapter 1: Background and Summary 46

47 The study is being conducted by the Pediatric Eye Disease Investigator Group (PEDIG) and is being 48 coordinated by the Jaeb Center for Health Research in Tampa, Florida. The study is funded through 49 a cooperative agreement from the National Eye Institute. 50 51 1.1 Objective 52 This study is designed to evaluate the effectiveness of treatment of residual amblyopia in children 53 ages 3 to <10 years with visual acuity of 20/32 to 20/63 in the amblyopic eye. The study is a 54 randomized clinical trial comparing intensive treatment (42 hours per week of patching plus daily 55 atropine) with a control group that will have rapid weaning of existing treatment followed by 56 spectacle correction only (if needed). The primary objective is to determine if intensive treatment 57 will improve visual acuity in patients with residual amblyopia. 58 59 1.2 Rationale for the Study 60 Amblyopia is the most common cause of monocular visual impairment in both children and young 61 and middle-aged adults. Both patching and atropine are accepted treatment modalities for the 62 management of moderate amblyopia in children.1 Despite best efforts with conventional treatment, 63 some patients fail to achieve normal visual acuity in the amblyopic eye. In a randomized trial 64 conducted by PEDIG comparing atropine versus patching in 3 to 6 year olds with moderate 65 amblyopia (ATS1), 261 of 402 patients (65%) had amblyopic eye visual acuity of 20/32 or worse 66 after 6 months of treatment with patching or atropine.1 Beyond 6 months, treatment was at 67 investigator discretion, and two years after randomization, 181 of 363 children (50%) still had 68 amblyopic eye visual acuity of 20/32 or worse.2 In a randomized trial conducted by PEDIG 69 comparing patching regimens, 129 of 181 patients with moderate amblyopia (71%) and 145 of 157 70 patients with severe amblyopia (92%) had amblyopic eye visual acuity of 20/32 or worse after 4 71 months of occlusion therapy.3,4 Many patients receive treatment beyond 6 months but still fail to 72 achieve normal visual acuity in the amblyopic eye. It is unknown whether an intensive “final push” 73 of combined treatment with daily patching and atropine will improve visual acuity in these patients. 74 Although some clinicians prescribe simultaneous patching and atropine for selected patients, there 75 are no published reports of its effectiveness. Also, we are not aware of reports of response to 76 treatment of residual amblyopia. 77 78 1.3 Synopsis of Study Design 79 Major Eligibility Criteria (see section 2.2 for a complete listing) 80

• Age 3 to < 10 years 81

• Amblyopia associated with strabismus, anisometropia, or both 82

• Visual acuity in the amblyopic eye between 20/32 and 20/63 inclusive 83

• Visual acuity in the sound eye 20/32 or better and inter-eye acuity difference >2 logMAR 84 lines 85

• Current/previous treatment with patching and/or atropine subject to the following 86 stipulations: 87

• No simultaneous treatment with patching and atropine in the past 6 months 88

• No prior use of atropine in combination with the sound eye spectacle lens reduced by 89 more than 1.50 D 90

• Maximum level of any previous treatment: 91

• Patching: up to 42 hours per week (averaging 6 hours daily) 92

• Atropine: up to once daily 93


• Current treatment with patching 42 hours per week or daily atropine 94

• No improvement in best-corrected amblyopic eye visual acuity between two consecutive 95 visits at least 6 weeks apart using the same testing method and optimal spectacle correction 96 (if needed), with no improvement defined as follows: 97

• No lines of improvement 98

• For patients tested using E-ETDRS, letter score that is no more than 4 letters improved 99

• Wearing spectacles with optimal correction (if applicable) 100

• Investigator ready to wean or stop treatment 101 102 Treatment Groups 103 Patients will be randomized to one of two treatment regimens: 104

• Intensive treatment: 42 hours per week of patching combined with daily atropine (1%) 105

• Control group: Weaning of the current treatment (two hours of daily patching for patients 106 currently using patching and once weekly atropine for patients currently using atropine) for 107 4 weeks, then no treatment other than spectacles (if needed) 108

109 Sample Size 110 One hundred twenty patients will be enrolled in each of the two treatment groups, for a total of 240 111 patients. This sample size will be sufficient to detect a 20% absolute difference between groups in 112 the proportion of patients with amblyopic eye visual acuity improving by 2 or more lines. 113 114 Contact and Visit Schedule 115

• Phone call at 4 weeks 116

• Primary outcome visit at 10 weeks 117

• If amblyopic eye acuity improved by >1 line (>5 letters) at primary outcome, follow-up 118 visits at 10 week intervals until no further improvement (>1 line), confirmed by a re-test 119

120 Additional visits can be performed at the discretion of the investigator. A Follow-up Examination 121 Form should be completed on the study website for every exam (not just the minimum required 122 exams). 123 124 Primary Analysis 125 The primary outcome assessment is amblyopic eye visual acuity at 10 weeks. 126 127 The primary analytic approach for the amblyopic eye acuity will be a treatment group comparison 128 of the proportion of patients with at least two lines of visual acuity improvement. 129

130


131 1.4 Study Summary Flow Chart 132

133 134

135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175

Major Eligibility Criteria

• Age 3 to <10 years old

• Amblyopic eye visual acuity 20/32 to 20/63

• Sound eye visual acuity >20/32

• IOD >2 lines

• Wearing spectacles with optimal correction (if applicable)

• No improvement in visual acuity on 2 consecutive exams at least 6 weeks apart (see 2.2 #6)

• Investigator ready to wean or stop treatment

• Current treatment: patching 42 hours per week or daily atropine

• Maximum previous treatment: 42 hours per week patching or daily atropine

• No simultaneous patching and atropine in past 6 months and no use of atropine ever with the sound eye lens reduced by more than 1.50 D.

• No strabismus surgery planned in next 10 weeks

Follow-up Visits

Every 10±1 weeks until no further improvement > 1 line, confirmed by re-test

• Visual acuity testing

• Assessment of ocular alignment

Weaning then Stop

2 hrs/day patching or once weekly atropine for 4 weeks, then stop

Patching averaging 6

hours daily plus daily

atropine (1%)

Primary Outcome Visit 10+1 weeks from baseline (2 weeks after discontinuation of atropine in intensive treatment group)

• Visual acuity testing by masked examiner


• Stereoacuity

End study

participation

No improvement

(confirmed by re-test) Improved by > 1 line

Baseline Visit

• Visual acuity testing


• Ocular exam (if not done within last 6 months)

• Cycloplegic refraction (if not done within last 6 months)

• Stereoacuity testing

Randomize to one of two groups


Chapter 2: Patient Enrollment (Baseline Visit) 176 177 2.1 Eligibility Assessment and Informed Consent 178 A patient is considered for the study after undergoing an eye examination by an investigator (as part 179 of standard care) that identifies amblyopia meeting the eligibility criteria. As noted in subsequent 180 sections, refractive error must be corrected with glasses (as per standard care) in most cases before a 181 patient can be enrolled into the trial. 182 183 For patients who appear eligible for the study following a “standard-care” examination, the study 184 will be discussed with the child’s parent(s) or guardian. Parents or guardians who express an 185 interest in the study will be given a brochure and a copy of the consent form. Written informed 186 consent will be obtained from the parent or guardian prior to performing any study-specific 187 procedures that are not part of the patient’s routine care. 188 189 2.2 Eligibility and Exclusion Criteria 190 The following criteria must be met for the patient to be enrolled in the study: 191 1. Age 3 to < 10 years 192

2. Amblyopia associated with strabismus (comitant or incomitant), anisometropia, or both 193

• Criteria for strabismus: At least one of the following criteria must be met: 194 � Heterotropia at distance and/or near fixation on examination (with or without 195

spectacles) 196

� History of strabismus surgery 197

� Documented history of strabismus which is no longer present (which in the judgment of 198 the investigator could have caused amblyopia) 199

• Criteria for anisometropia: At least one of the following criteria must be met: 200 � >0.50 D difference between eyes in spherical equivalent 201

� >1.50 D difference between eyes in astigmatism in any meridian 202

3. Sound eye has no myopia of -0.50 D or more (spherical equivalent). 203

4. Amblyopic eye has no myopia of -6.00 D or more (spherical equivalent). 204

5. Visual acuity, measured in each eye without cycloplegia within 7 days prior to randomization 205 using the ATS single-surround HOTV letter protocol for children ages 3 to <7 and the E-206 ETDRS protocol for children ages 7 to <10 on Electronic Visual Acuity Tester as follows: 207

• Visual acuity in the amblyopic eye between 20/32 and 20/63 inclusive 208

• Visual acuity in the sound eye 20/32 or better 209

• Inter-eye acuity difference >2 logMAR lines (i.e., amblyopic eye acuity at least 2 lines 210 worse than sound eye acuity) 211

6. No improvement in best-corrected amblyopic eye visual acuity while on therapy (see #7) 212 between two consecutive visits at least 6 weeks apart using the same testing method and optimal 213 spectacle correction (if needed), with no improvement defined as follows: 214

• No lines of improvement 215

• For patients tested using E-ETDRS, letter score that is no more than 4 letters improved 216

7. Current treatment: Patching 42 hours per week or daily atropine 217

8. Previous amblyopia treatment: 218


• Maximum level of any previous treatment: patching up to 42 hours per week or atropine up 219 to once daily 220

• No simultaneous treatment with patching and atropine in the past 6 months (including, for 221 example, treatment with patching on weekdays and atropine on weekends), and no use of 222 atropine ever with the sound eye lens reduced by more than 1.50 D. 223

9. Spectacle correction (if applicable) for measurement of enrollment visual acuity must meet the 224 following criteria and be based on a cycloplegic refraction that is no more than 6 months old: 225

226 a. Requirements for spectacle correction: 227

• Spherical equivalent must be within 0.50 D of fully correcting the anisometropia 228

• Hypermetropia must not be undercorrected by more than 1.50 D spherical 229 equivalent, and reduction in plus sphere from the most recent cycloplegic 230 refraction must be symmetric in the two eyes 231

• Cylinder power in both eyes must be within 0.50 D of fully correcting the 232 astigmatism 233

• Cylinder axis in both eyes is within 6 degrees of the axis in the spectacles when 234 cylinder power is > 1.00 D. 235

• Myopia of amblyopic eye greater than 0.50 D by spherical equivalent must be 236 corrected, and the glasses must not undercorrect the myopia by more than 0.25 D 237 or overcorrect it by more than 0.50 D. 238

239 10. No current vision therapy or orthoptics 240

11. No ocular cause for reduced visual acuity 241 • nystagmus per se does not exclude the patient if the above visual acuity criteria are met 242

12. Ocular examination within 6 months prior to enrollment 243

13. No prior intraocular or refractive surgery 244

14. No strabismus surgery planned for at least 10 weeks 245

15. No known allergy to atropine or other cycloplegic drugs 246

16. No known skin reactions to patch or bandage adhesives 247

17. Down Syndrome not present 248

18. Parent willing to accept randomized treatment, available for at least 3 months of follow-up, has 249 home phone (or access to phone), and willing to be contacted by Jaeb Center staff 250

19. Investigator is ready to wean or stop treatment. 251

20. In the investigator’s judgment, the child is likely to comply with prescribed treatment. (e.g. no 252 history of poor compliance with patching or atropine treatment) 253

21. In the investigator’s judgment, amblyopic eye acuity has improved with previous treatment, 254 which can include improvement with spectacles. 255

256

2.3 Examination Procedures 257 2.3.1 Historical Information 258 Historical information elicited will include the following: date of birth, gender, ethnicity, prior 259 amblyopia therapy (e.g., glasses, patching, pharmacologic, Bangerter filters, combined therapies, 260 near activities with treatment), corrected visual acuity before amblyopia treatment started (if 261


available), current amblyopia therapy, current spectacle correction, and history of allergy to 262 adhesive skin patches or to cycloplegic eye drops. 263 264 2.3.2 Clinical Testing 265 Examination procedures include: 266 1. Measurement of visual acuity in each eye (right eye first) by the ATS single-surround HOTV 267

testing protocol for children ages 3 to <7 and the E-ETDRS for children ages 7 to <10 on the 268 Electronic Visual Acuity (EVA) Tester. 269

• The ATS-HOTV and E-ETDRS visual acuity protocols must be used throughout the study. 270 The protocol for conducting the visual acuity testing is described in the ATS Testing 271 Procedures Manual. Aspects of the testing protocol that are specific to this study are: 272

• Testing of the amblyopic eye must be done without cycloplegia (with spectacles, if 273 worn) no more than 7 days prior to randomization. 274

• Patients currently wearing spectacles must have enrollment acuity measured while 275 wearing spectacles -trial frames or phoropter cannot be used. 276

• If the sound eye is atropinized, then the best-corrected (based on the most recent 277 refraction) sound eye visual acuity will be measured by placing the appropriate 278 refractive correction before the sound eye (e.g., using lenses in trial frames if needed). 279

2. Ocular motility examination 280 • Measurement of alignment by Simultaneous Prism and Cover Test (SPCT) in primary 281

position at distance and near 282 • If performed within prior 7 days, it does not need to be repeated at time of enrollment 283

3. Stereoacuity testing: Titmus fly, Randot Preschool test (no plus lenses are added for testing; if 284 the child is currently on atropine, results will be interpreted in this context) 285

4. Complete ocular examination, including dilated fundus examination, to rule out a cause for 286 reduced visual acuity other than amblyopia. 287

• If performed within prior 6 months, it does not need to be repeated at time of enrollment 288

5. Cycloplegic refraction using cyclopentolate 1% as per investigator’s usual routine 289

• If performed within prior 6 months, it does not need to be repeated at time of enrollment 290 291 2.4 Randomization of Eligible Patients 292 1. Once a patient is randomized, that patient will be included in the analysis regardless of whether 293

the assigned treatment is received or not. Thus, the investigator must not randomize a patient 294 until he/she is convinced that the parent/guardian will accept and comply with either of the 295 treatment regimens. 296

2. Treatment per protocol must commence within 48 hours following randomization; therefore, a 297 patient should not be randomized until both the investigator and parent are ready to start 298 protocol-mandated treatment. 299

3. The Jaeb Center will construct a Master Randomization List using a permuted block design 300 stratified by site and current treatment, which will specify the order of treatment group 301 assignments. A patient is officially enrolled when the website randomization process is 302 completed. 303

304 2.4.1 Delay in Randomization 305 1. Visual acuity testing and the ocular motility examination must be performed no more than 7 306

days prior to randomization. If randomization is delayed beyond 7 days, then these tests must 307 be repeated to confirm eligibility and establish the baseline measures for the study. 308


2. No other parts of the examination (including the refraction) need to be repeated if they were 309 performed within 6 months prior to randomization. 310

311 2.4.2 Reading Glasses 312 313 Children who are attending school and who experience difficulty with school work while on 314 treatment will be prescribed separate reading glasses (single vision spectacles with +2.50 added to 315 distance correction for both eyes, or a different amount at investigator discretion). The glasses will 316 be used for near work in school and at home and they will be paid for by the study. Parents of 317 children randomized to intensive treatment will be instructed to inform their doctor if there are 318 problems with school work.319


Chapter 3: Treatment and Follow Up 320 321 3.1 Treatment Groups 322 Each patient will be randomly assigned to one of two groups: 323

• Intensive treatment group 324 o 42 hours per week of patching plus atropine 1% once daily in the sound eye, with 325

spectacle correction (if needed), and with at least one hour of near activities during 326 patching 327

o Atropine is discontinued after 8 weeks (2 weeks prior to 10-week visit, see section 328 3.2) so that stereopsis and sound eye acuity can be determined at the 10-week 329 primary outcome visit. Atropine will be restarted immediately following the 10-330 week visit for patients continuing in the study. 331

• Control group 332 o For patients currently patching, reduce patching to two hours daily for four weeks, 333

then no treatment thereafter except spectacle correction (if needed) 334 o For patients currently using atropine, reduce atropine to once weekly for 4 weeks, 335

then no treatment thereafter except spectacle correction (if needed) 336 o Near activities are not prescribed during patching or atropine therapy 337

338 For both the intensive treatment group and the control group: 339

• Treatment is continued until there is no further improvement in amblyopic eye acuity 340 (improvement defined as >1 line or >5 letters) between two consecutive 10-week visits, 341 confirmed by a re-test. Once there is no further improvement, the patient’s participation in 342 the study is over and treatment is at investigator discretion. 343

344 Notes 345 1. The study will be providing patches and atropine. 346

2. Children using atropine will be encouraged to wear a hat with a brim for outdoor activities. 347 Nonprescription sunglasses, clip-ons, or flip-ups will be provided by the study. 348

3. Morning is the preferred time for administration of atropine. However, it is acceptable to 349 administer the atropine at night if the parent/guardian has an overriding reason for it. 350

4. If an allergy to atropine develops, the patient can be switched to homatropine 5% after 351 discussion with the Protocol Chair (see section 4.7.1 #6). 352

5. If a patient is noncompliant with treatment, the parents should be encouraged to persist with 353 their efforts to treat to the best of their ability. 354

6. Prior to deviating from the treatment protocols or prescribing non-protocol treatment, the 355 situation should be discussed with the Protocol Chair. 356

357 3.1.1 Compliance 358 A calendar log will be maintained by all patients on atropine and/or patching treatment, including 359 those in the control group. These logs will be reviewed by the investigator at each of the protocol 360 visits. The investigator’s assessment of compliance will be recorded on the Follow-up Examination 361 Form. 362 363 3.2 Follow-up Examinations 364 All patients will have the following study visits / interactions: 365

• 4 week: telephone call 366


• 10 + 1 week: primary outcome visit 367

• For patients whose amblyopic eye acuity has improved by >1 line (>5 letters) at the 10-week 368 primary outcome visit, visits will occur every 10 + 1 week until no further improvement >1 line 369 (>5 letters), confirmed by a re-test, at which point study participation ends and treatment is at 370 investigator discretion 371

372 Visit / Interaction

Test

Baseline 4 wk Primary

Outcome

10 + 1 wk

Every 10+ 1

wks after

primary

outcome**

Telephone call X

Distance acuity each eye* X X X

Ocular alignment X X X

Titmus Fly X X

Randot Preschool Test X X

*Using ATS single-surround HOTV acuity testing protocol for children ages 3 to <7 and the E-373 ETDRS for children ages 7 to <10 on the EVA. The acuity testing at the 10-week primary outcome 374 visit will be done by a masked examiner. 375 **For patients whose amblyopic eye acuity has improved by >1 line (>5 letters) at the 10-week 376 primary outcome visit. Visits occur every 10 + 1 week until no further improvement >1 line (>5 377 letters). 378

379 Additional visits can be performed at the discretion of the investigator. A Follow-up Examination 380 Form should be completed on the study website for every exam (not just the minimum required 381 exams). 382 383 For those patients in the intensive treatment group, atropine will be discontinued 8 weeks after 384 randomization, which is two weeks before the 10-week primary outcome visit. Atropine will be 385 started again immediately following the 10-week primary outcome visit for those patients 386 continuing in the study. 387

388 3.2.1 Telephone Call 389 Each patient will be contacted by the coordinating center via telephone shortly after enrollment and 390 then again 4 weeks following randomization. Parents of patients in the control group will be 391 reminded to discontinue weaning treatment at this time. Parents of patients in the intensive 392 treatment group will be encouraged to continue treatment and reminded to discontinue atropine 2 393 weeks before the 10-week primary outcome visit. 394 395 3.2.2 Letter Reminder 396 A letter will be sent to all patients in the intensive treatment group 3 weeks before the 10-week 397 primary outcome exam (to be received approximately 2 weeks before the outcome exam). The 398 purpose of this letter is to remind parents to discontinue atropine treatment 2 weeks prior to the 10-399 week primary outcome exam. 400 401 3.2.3 Primary Outcome Visit 402 The primary outcome visit will occur at 10+1 weeks, 2 weeks after the intensive treatment group 403 discontinues atropine. 404 405 Testing will include the following: 406

1. Visual acuity 407


• Measured in each eye (amblyopic eye first) by a certified masked examiner using the 408 ATS single-surround HOTV acuity protocol for children ages 3 to <7 and E-ETDRS 409 protocol for children ages 7 to <10 on the Electronic Visual Acuity (EVA) Tester 410

• In the event that the sound eye is still atropinized (i.e., the parent or guardian has 411 forgotten to discontinue atropine), then the best-corrected sound eye visual acuity will be 412 measured by placing the appropriate refractive correction before the sound eye (e.g., 413 using lenses in trial frames) 414

2. Titmus fly and Randot Preschool Stereoacuity test 415

• In the event that the sound eye is still atropinized, then stereoacuity will not be tested. 416 3. Ocular alignment assessed with the SPCT 417

• In the event that the sound eye is still atropinized, then ocular alignment will still be 418 assessed, but results will be interpreted in the context of cycloplegia. 419

4. Retesting of visual acuity in the amblyopic eye (if indicated) 420

• If amblyopic eye visual acuity has not improved from randomization by at least one line 421 (>5 letters), then it will be re-tested. 422

• The results of the re-test will be used only to determine if the patient will continue study 423 participation with the same study-mandated treatment. The first visual acuity will be 424 used as the primary outcome visual acuity. If neither the test nor the re-test is one line 425 (>5 letters) better than the visual acuity at randomization, then study participation ends. 426

5. Retesting of visual acuity in the sound eye (if indicated) 427

• If sound eye visual acuity is reduced by one or more lines (5 or more letters) from its 428 baseline acuity, then it will be re-tested. 429

• If the better sound eye visual acuity of the test and the re-test is decreased by 430 one line (5-9 letters) from baseline, and if amblyopic eye acuity has improved 431 by > 1 line (>5 letters), then the patient will continue with the same study-432 mandated treatment. 433

• If the better sound eye visual acuity of the test and re-test is 2 or more lines 434 down from baseline (10 or more letters worse than baseline), then a 435 cycloplegic refraction should be performed, and if a change in the refraction 436 has occurred, then the appropriate lenses should be placed in trial 437 frames/phoroptor, and the acuity should be re-tested. 438

� If the best-corrected acuity is still reduced by 2 or more lines from 439 baseline (10 or more letters worse than baseline) and there has been a 440 significant change in refraction (as defined in Section 2.2 #9), then a 441 change in spectacle lens should be prescribed (the study will pay for 442 this change). 443

� If the best sound eye acuity at the outcome exam is decreased 2 or 444 more lines from baseline (10 or more letters worse than baseline), 445 then study-mandated treatment may end (per investigator discretion), 446 and the patient should return in 5 weeks to recheck the sound eye 447 acuity. This additional visit will occur regardless of whether there was 448 a change in sound eye refraction and/or there was an improvement in 449 the amblyopic eye at the outcome exam. 450

451 3.2.4 Follow-Up Visits after the Primary Outcome 452 For patients in either treatment group with at least one line (>5 letters) of improvement in 453

amblyopic eye acuity at the primary outcome examination, follow-up visits will occur every 10 ± 1 454 weeks until no further improvement ≥1 line (>5 letters) is seen. 455 456


In contrast to the 10-week primary outcome visit, atropine is not discontinued for the post-primary 457 outcome follow-up exams, because stereopsis is not assessed at these visits. 458 459 Testing will include the following: 460

1. Visual Acuity 461

• Measured in each eye (right eye first) by a certified examiner using the ATS single-462 surround HOTV acuity protocol for children ages 3 to <7 and the E-ETDRS protocol for 463 children ages 7 to <10 on the Electronic Visual Acuity (EVA) Tester. 464

• Because the sound eye of those patients in the intensive treatment group will be 465 atropinized, best-corrected sound eye visual acuity will be measured by placing the 466 appropriate refractive correction (equal to the most recent cycloplegic refraction) before 467 the sound eye (e.g., using lenses in trial frames if needed). 468

• Visual acuity in the amblyopic eye will be retested if visual acuity has not improved 469 from the last visit by at least one line (>5 letters). 470

• Visual acuity in the sound eye will be retested if visual acuity has decreased by one or 471 more lines (>5 letters) from baseline, using the same protocol as the 10-week primary 472 outcome examination – see section 3.2.3. 473

2. Ocular alignment assessed with the SPCT 474 475

Study participation will end only after a post-primary outcome follow-up visit at which 476 amblyopic eye acuity shows no further improvement >1 line (>5 letters) on both an initial test 477 and on a confirmatory retest (or at investigator discretion if there is a reduction in best sound 478 eye acuity of > 2 lines (>10 letters) from baseline).479


Chapter 4: Miscellaneous Considerations 480 481 4.1 Management of Optical Correction 482 A refraction should be performed at any time the investigator suspects that refractive error may not 483 be optimally corrected. A change in spectacle correction is at investigator discretion. 484 485 4.2 Management of Strabismus 486 Strabismus surgery should not be done for 10 weeks after randomization, and it is allowed at the 487 discretion of the clinician thereafter. Surgery will be recorded in the comment section of the 488 Follow-up Examination Form. 489 490 4.3 Worsening of Visual Acuity in the Amblyopic Eye 491 If visual acuity should worsen in the amblyopic eye (or in the sound eye and does not recover with 492 cessation or reversal of treatment), the investigator should evaluate this condition using best clinical 493 judgment and perform whatever work-up is clinically indicated to assess for an alternate cause (i.e., 494 other than amblyopia) for the visual loss. Patients found to have a cause other than amblyopia that 495 fully explains the visual loss (i.e., amblyopia was never present) will be dropped from the study. 496 This will be reported on the Patient Final Status Form. 497

498 4.4 Patient Withdrawals 499 A parent or guardian may withdraw a patient from the trial at any time. This is expected to be a 500 very infrequent occurrence in this trial in view of the testing procedures’ similarity to routine 501 clinical practice. If the parents or guardian indicate that they want to withdraw the child from the 502 study, the investigator should attempt to speak with them to determine the reason. 503 504 4.5 Risks 505 There are no risks involved in this study that would not be part of usual care in which the study 506 treatments were administered. 507 508 4.6 Risks of Examination Procedures 509 The procedures in this study are part of daily pediatric eye care practice in the United States and 510 pose no known risks. As part of a routine usual-care exam, the patient may receive 511 cycloplegic/dilating eye drops. 512 513 4.7 Adverse Events/Risks 514 The risks involved in the study are identical to those that would be present for a patient treated with 515 the study treatment regimens who is not participating in the study. 516 517 4.7.1 Side Effects of Treatment 518 1. Patching and/or atropine potentially could decrease the visual acuity in the sound eye, although 519

this is almost always reversible. The diagnosis and management of reverse amblyopia is left to 520 the investigator’s judgment- see section 4.7.2. 521

522 2. If skin irritation occurs, the parent will be advised to put an emollient on the skin and 523

discontinue use of the patch for a day. If a skin reaction to the patch or an allergic reaction 524 occurs serious enough to discontinue patching prior to the 10-week outcome exam, the 525 investigator will call the Protocol Chair to discuss the case. An alternative adhesive patch may 526 be tried. If patching with adhesive patches is discontinued, then the patient should try a Patch 527 Works occluder on glasses (using plano lenses if the patient is not wearing spectacles). 528


529 3. Patching could precipitate the development of an ocular deviation. See Section 4.7.3. 530

531 4. Following atropine, local side effects of minimal severity include allergic lid reactions, local 532

irritation, conjunctival hyperemia, and follicular conjunctivitis. Potential systemic side effects 533 include dry skin and mouth, tachycardia, fever, flushing and irritability. These effects are very 534 uncommon using the dosage schedule (up to one drop daily) in this protocol as noted in the 535 previous studies of atropine treatment. In ATS1,1 among 204 patients, an ocular side effect 536 was reported at least once for 26% of patients, most commonly light sensitivity (18%), lid or 537 conjunctival irritation (4%), and eye pain or headache (2%). Facial flushing was reported for 538 two patients, one of whom remained on atropine with no further problems and one of whom 539 was switched to homatropine. Atropine was not discontinued because of side effects in any 540 other patients. No other systemic side effects of atropine were reported. Ocular side effects in 541 ATS4, most commonly light sensitivity, were reported by 13 patients (16%) in the daily group 542 and 25 patients (29%) in the weekend group.7 However, these symptoms did not lead to a 543 change in treatment. Facial flushing and fever were reported for 2 patients in the daily group; 544 one of these patients remained on atropine and the other was switched to homatropine. 545

546 5. Atropine produces dilation of the pupil, which can increase the light that enters the eye. 547

Although it has not been demonstrated that atropine used for several months will have harmful 548 ocular effects, excessive exposure to light theoretically could be toxic to the retina. Atropine 549 has been used long-term to prevent the progression of myopia without an apparent adverse 550 effect on acuity.6,8-10 To minimize risks from pupil dilation, sunglasses, clip-ons, or flip-ups 551 will be provided. Hats with brims or visors will be encouraged. 552

553 6. When a patient develops adverse effects serious enough to discontinue atropine prior to the 554

primary outcome exam, the investigator should call the Protocol Chair to discuss the case. If 555 atropine is discontinued, then the patient could be switched to homatropine 5%. The following 556 guidelines should be followed after discussion with the Protocol Chair: 557

• If a patient has a serious systemic adverse effect of atropine (such as seizure), an 558 atropine-like drug should not be prescribed. 559

• If a patient has mild effects that may be due to atropine such as facial flushing, then 560 homatropine should be substituted. Initially, one drop is given. If there is no 561 adverse effect in three days, then a second drop is given. If no problem in three 562 days, the dosing is increased to 7 days per week. Drops should be administered in 563 the morning. 564

565 4.7.2 Reverse Amblyopia 566 Atropine and patching could decrease the visual acuity in the sound eye, although this is almost 567 always reversible. In ATS1, results were inconclusive as to whether atropine produced a transient 568 decrease in sound eye acuity. However, the results indicated that treatment did not cause a 569 permanent reduction in sound eye acuity. After two years of follow up, there was no difference in 570 sound eye acuity between the two treatment groups. 571 572 The diagnosis and management of reverse amblyopia at each of the study visits is left to the 573 investigator’s judgment. At the primary outcome visit and subsequent follow-up visits (if 574 indicated), a protocol will be followed for retesting and evaluating the sound eye if it has reduced 575 vision (see section 3.2.3). 576 577


4.7.3 Development of Strabismus 578 The study treatment could precipitate the development of a new manifest ocular deviation. If 579 treatment precipitates the development of an ocular deviation (e.g., esotropia), the parent(s) will be 580 advised to have the patient see the investigator as soon as possible. If the development of a new 581 deviation is confirmed on examination, the decision as to whether to continue or discontinue 582 therapy will be left to the investigator. If amblyopia treatment is to be discontinued prior to the 583 primary outcome exam, then the Protocol Chair should be called to discuss the situation. The 584 development of a new heterotropia is an accepted risk of standard-care amblyopia therapy. 585 However, previous studies suggest that the resolution of pre-existing strabismus during amblyopia 586 treatment occurs as often as the development of new strabismus. In ATS1, new strabismus occurred 587 in 13% of patching patients and in 13% of those using atropine. Twenty-one percent of patients had 588 resolution of their preexisting strabismus with treatment. In ATS4, 10% of patients had a new 589 strabismus or a worsening of a pre-existing strabismus by > 10 pd, and 8% were found to have 590 resolution of their preexisting strabismus or reduction in their strabismic angle by > 10 pd. This 591 risk in this study is no greater than it would be with standard care of amblyopia. 592 593 In view of the short duration of the study and the eligibility criterion that strabismus surgery is not 594 planned in the next 10 weeks, it is unlikely that strabismus surgery will need to be performed prior 595 to the 10-week primary outcome exam. However, such surgery is allowed at the discretion of the 596 clinician if medically indicated following the 10-week primary outcome exam. 597 598 4.8 Reporting of Adverse Events 599 Each investigator is responsible for informing his/her IRB of serious treatment-related adverse 600 events and for abiding by any other reporting requirements specific to his/her IRB. 601

Data on the complications of the study treatments will be tabulated regularly by the Coordinating 602 Center for review by the Steering Committee. Serious, treatment-related complications will be 603 reported expeditiously to the Data and Safety Monitoring Committee, which will receive a full 604 adverse event report semi-annually. Following each DSMC data review, a summary will be 605 provided to IRBs. 606 607

4.9 Patient Payments 608 The parent/guardian of each patient will be compensated $25 per visit for completion of the 609 enrollment visit and the primary outcome visit. For patients remaining in follow up after the 10-610 week visit, $25 will be paid for each 10-week interval visit, up to an additional $100 (4 exams). The 611 total maximum compensation for the study is $150. If there are extenuating circumstances, 612 additional funds may be provided for travel if expenses exceed $25 and the patient will be unable to 613 complete the visit without the reimbursement of the travel expenses. All payments will be made by 614 the Jaeb Center by the month following the date of each completed visit. 615 616 4.10 Discontinuation of Study 617 The study may be discontinued by the Steering Committee (with approval of the Data and Safety 618 Monitoring Committee) prior to the preplanned completion of enrollment and follow-up for all 619 patients. 620 621 4.11 Contacts by the Jaeb Center for Health Research 622 The Jaeb Center serves as the PEDIG Coordinating Center. The Jaeb Center will be provided with 623 the parent/guardian’s contact information. The Jaeb Center will maintain direct contact with the 624 parents or guardian of each patient. Permission for such contacts will be included in the Informed 625 Consent Form. The principal purpose of the contacts will be to develop and maintain rapport with 626


the family and to help coordinate scheduling of the outcome examination. One initial phone contact 627 is planned for each patient shortly after randomization and a second phone contact will occur 4 628 weeks after randomization. Additional phone contacts will be made if necessary to facilitate the 629 scheduling of the patient for follow-up visits. A letter will be sent to the parents or guardian of each 630 patient in the intensive treatment group 3 weeks before the 10-week primary outcome exam, 631 reminding them to discontinue atropine 2 weeks before the outcome exam. A patient newsletter, 632 study updates, and a study logo item may be sent. Patients will be provided with a summary of the 633 study results in a newsletter format after completion of the study by all patients. 634 635


Chapter 5: Sample Size Estimation and Statistical Analysis 636 637 The estimation of sample size and statistical analysis plan are summarized below and detailed in 638 separate documents. 639 640 5.1 Sample Size Estimation 641 ATS2C studied the recurrence rate of amblyopia in 3 to <8 year-old children with successfully 642 treated anisometropic or strabismic amblyopia. In that study, approximately 15% of patients with 643 enrollment acuity of 20/32 to 20/50 inclusive had their visual acuity improve by 2 or more lines 13 644 weeks after stopping treatment. Taking a more conservative approach, we estimate that 20% of 645 patients in the current study’s control group will improve by 2 or more lines. Following discussion 646 among clinicians on the planning committee as to what minimum increase in the proportion of 647 improving patients would be considered clinically significant, and considering the increased 648 inconvenience to patients of intensive treatment, an effect size of 20% was accepted (improvement 649 of 20% in the control group vs. 40% in the intensive treatment group). Assuming a 2-tailed test 650 with an alpha of 0.05 at 90% power, and given that those lost to follow-up will be considered to 651 have not improved 2 or more lines, the sample size has been calculated to be 120 per group (240 652 total). 653 654 5.2 Primary Analysis 655 The primary analyses will include all patients enrolled in the study. The primary analysis will be a 656 treatment group comparison of the proportion of patients with at least two lines of visual acuity 657 improvement between randomization and the 10-week primary outcome visit using logistic 658 regression, adjusting for baseline acuity. 659 660 5.3 Secondary Analyses 661 Because patients in both groups who improve at least one line after 10 weeks will continue in 662 follow-up, a secondary analysis will be a treatment group comparison of the proportion of patients 663 with at least two lines of visual acuity improvement between randomization and the last follow-up 664 visit using logistic regression, adjusting for baseline acuity. 665 666 Secondary analyses will also include a treatment group comparison of logMAR visual acuity scores 667 in the amblyopic eye at the primary outcome visit and at the last follow-up visit, adjusted for 668 baseline visual acuity scores in an analysis of covariance (ANCOVA) model. 669 670 The treatment effect in subgroups based on baseline factors will be explored. The subgroups of 671 interest are those based on baseline visual acuity, cause of amblyopia, age, visual acuity prior to 672 starting amblyopia treatment, stereoacuity (in those patients not using atropine at baseline), and 673 prior treatment, including treatment immediately before randomization (patching vs. atropine). For 674 determining cause of amblyopia for analysis purposes, amblyopia associated with strabismus or 675 with anisometropia will be defined as explained in section 2.2 #2. Combined mechanism 676 amblyopia will be defined using the following criteria: 677 678

• Both of the following criteria must be met: 679 � Criteria for strabismus are met (see section 2.2 #2) 680 � >1.00 D difference between eyes in spherical equivalent or >1.50 D difference between 681

eyes in astigmatism in any meridian 682 683 684


5.4 Safety Analysis 685 Safety data consisting of the number and proportion of patients in each treatment group 686 experiencing the following events will be compiled and included in all reports to the DSMC: 687

• Loss of 2 or more lines (>10 letters) in sound eye visual acuity from baseline to the 10-week 688 outcome exam and from baseline to any follow-up exam 689

• Development of a new ocular deviation or an increase by 10 or more prism diopters in an 690 existing near or distance tropia evident at the 10-week outcome exam 691


Chapter 6: References 692 693 1. Pediatric Eye Disease Investigator Group. A randomized trial of atropine vs patching for 694

treatment of moderate amblyopia in children. Arch Ophthalmol 2002; 120:268-78. 695 2. Pediatric Eye Disease Investigator Group. Two-year follow-up of a 6-month randomized 696

trial of atropine vs patching for treatment of moderate amblyopia in children. Arch 697 Ophthalmol 2005;123:149-57. 698

3. Pediatric Eye Disease Investigator Group. A randomized trial of atropine regimens for 699 treatment of moderate amblyopia in children. Ophthalmology 2004; 111:2076-85. 700

4. Pediatric Eye Disease Investigator Group. A randomized trial of patching regimens for 701 treatment of moderate amblyopia in children. Arch Ophthalmol 2003; 121:603-11. 702

5. Simons K, Stein L, Sener EC, Vitale S, Guyton DL. Full-time atropine, intermittent 703 atropine, and optical penalization and binocular outcome in treatment of strabismic 704 amblyopia. Ophthalmology 1997; 104:2143-55. 705

6. Brodstein RS, Brodstein DE, Olson RJ, Hunt SC, Williams RR. The treatment of myopia 706 with atropine and bifocals: a long-term prospective study. Ophthalmology 1984; 91:1373-9. 707

7. Pediatric Eye Disease Investigator Group. The course of moderate amblyopia treated with 708 atropine in children: experience of the Amblyopia Treatment Study. Am J Ophthalmol 2003; 709 136:630-39. 710

8. Kennedy RH, Dyer JA, Kennedy MA, et al. Reducing the progression of myopia with 711 atropine: a long term cohort study of Olmsted County students. Binoc Vis Quart 2000; 712 15:281-304. 713

9. Bedrossian RH. The effect of atropine on myopia. Ophthalmology 1979; 86:713-7. 714 10. Chiang MF, Kouzis A, Pointer RW, Repka MX. Treatment of childhood myopia with 715

atropine eye drops and bifocal spectacles. Binocul Vis Strabismus Q 2001; 16:209-15. 716 717

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