A Prospective Observational Study of Adult Strabismus
Conditions: Convergence Insufficiency, Divergence Insufficiency, Hypertropia
Sponsor: Jaeb Center for Health Research

 
SAS1 Protocol v2.0 4-11-16 
 
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STUDY OF ADULT STRABISMUS 
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(SAS1) 
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A Prospective Observational Study of Adult 
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Strabismus 
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SAS1a: A Prospective Observational Study of Adult Convergence Insufficiency (CI) 
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SAS1b: A Prospective Observational Study of Adult Divergence Insufficiency (DI) 
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SAS1c: A Prospective Observational Study of Adult Small-Angle Hypertropia (HT) 
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PROTOCOL 
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Version 2.0 
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April 11, 2016 
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SAS1 Protocol v2.0 4-11-16 
A PROSPECTIVE OBSERVATIONAL STUDY OF ADULT STRABISMUS (SAS1) 
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PROTOCOL AMENDMENT I (4-11-16) 
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Proposed Change #1 
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Current Protocol 
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• Enrollment visit:  Questionnaires and the symptom survey (if applicable) should be 
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administered to the subject prior to other examination procedures. 
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• Follow-up visits:  No specific mention regarding order of testing with respect to 
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questionnaires and the symptom survey. 
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Proposed Change 
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• Enrollment visit:  Remove specific language regarding order of testing to allow 
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questionnaires and the symptom survey (if applicable) to be completed at any time during 
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the enrollment visit.   
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• Follow-up visits:  Add specific language regarding order of testing at follow-up visits to 
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require questionnaires and the symptom survey (if applicable) to be completed prior to 
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testing.   
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Rationale for Change 
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At the time of enrollment, treatment has not yet been initiated, therefore having knowledge of 
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clinical assessments prior to completion of the questionnaires and the symptom survey is not 
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expected to introduce any bias.  In contrast, the questionnaires and symptom survey should be 
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completed prior to clinical testing at any follow-up visit.  
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Proposed Change #2 
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Current Protocol – For subjects enrolled with Divergence Insufficiency 
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Distance esodeviation of 2 PD to 30 PD and at least 50% greater than at near by PACT 
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Proposed Change – For subjects enrolled with Divergence Insufficiency 
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Distance esodeviation of 2 PD to 30 PD and distance deviation is at least 1.25 times (25% larger 
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than) near deviation by PACT (i.e., maximum near deviation is at least 20% smaller than 
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distance deviation). The distance deviation must exceed the near deviation by at least the 
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amounts provided in the table below. 
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PACT Values for DI Eligibility  
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Distance 
Deviation 
2 
3 
4 
5 
6 
7 
8 
9 
10 12 14 16 18 20 25 30 
*Max Near 
Deviation 
1 
2 
3 
4 
4 
5 
6 
7 
8 
9 
10 12 14 16 20 20 
Calculation: Distance ≥ Near x 1.25 or Near ≤ Distance x 0.8 
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*Near deviation is the nearest study-permitted prism based on Strabismus Procedures Manual. 
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Rationale for Change 
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The previous DI definition was developed by the SAS1 Planning Committee after literature 
73 
review and chart reviews.  After the study started, the Strabismus Steering Committee has 
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lowered the threshold based on feedback from SAS1 investigators. 
 
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SAS1 Protocol v2.0 4-11-16 
 
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CONTACT INFORMATION 
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COORDINATING CENTER 
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Raymond T. Kraker, M.S.P.H. (Director) 
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Jaeb Center for Health Research 
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15310 Amberly Drive, Suite 350 
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Tampa, FL 33647 
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Phone (888) 79PEDIG or (813) 975-8690 
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Fax (888) 69PEDIG or (813) 975-8761 
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Email: pedig@jaeb.org 
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PROTOCOL CHAIR 
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Eric Crouch, M.D. 
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Virginia Pediatric Eye Center 
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880 Kempsville Road, Suite 2500 
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Norfolk, VA 23502 
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Phone (757) 461-0050 
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Fax (757) 461-4538 
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Email: ercrouch@virginiapediatriceye.com 
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SAS1 Protocol v2.0 4-11-16 
TABLE OF CONTENTS 
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CHAPTER 1: BACKGROUND AND SUMMARY ....................................................................................................... 1-1 
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1.1 
Background .............................................................................................................................................. 1-1 
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1.2 
Rationale for the study ............................................................................................................................. 1-2 
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1.3 
Considerations .......................................................................................................................................... 1-2 
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1.4 
Study Objectives ...................................................................................................................................... 1-3 
106 
1.5 
Synopsis of Study Design ........................................................................................................................ 1-3 
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1.5.1 
Synopsis of Study Design for CI ......................................................................................................... 1-3 
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1.5.2 
Study Flow Chart: CI ........................................................................................................................... 1-5 
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1.5.3 
Synopsis of Study Design for DI ......................................................................................................... 1-6 
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1.5.4 
Study Flow Chart: DI ........................................................................................................................... 1-8 
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1.5.5 
Synopsis of Study Design for HT ........................................................................................................ 1-9 
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1.5.6 
Study Flow Chart: HT........................................................................................................................ 1-11 
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CHAPTER 2: SUBJECT ENROLLMENT .................................................................................................................. 2-12 
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2.1 
Eligibility Assessment and Informed Consent ....................................................................................... 2-12 
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2.2 
Eligibility and Exclusion Criteria ........................................................................................................... 2-12 
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2.2.1 
Eligibility Criteria for CI ................................................................................................................... 2-12 
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2.2.2 
Eligibility Criteria for DI ................................................................................................................... 2-13 
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2.2.3 
Eligibility Criteria for HT .................................................................................................................. 2-14 
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2.3 
Historical Information ............................................................................................................................ 2-14 
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2.4 
Procedures at the Enrollment Visit ......................................................................................................... 2-15 
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2.4.1 
Enrollment Procedures for CI ............................................................................................................ 2-15 
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2.4.2 
Enrollment Procedures for DI ............................................................................................................ 2-16 
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2.4.3 
Enrollment Procedures for HT ........................................................................................................... 2-16 
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CHAPTER 3: TREATMENT AND FOLLOW-UP ....................................................................................................... 3-1 
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3.1 
Treatment ................................................................................................................................................. 3-1 
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3.2 
Visit Schedule .......................................................................................................................................... 3-1 
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3.3 
Follow-up Visit Testing Procedures (10-week and 12-month visits) ....................................................... 3-1 
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3.3.1 
Follow-up Visit Testing Procedures for CI .......................................................................................... 3-1 
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3.3.2 
Follow-up Visit Testing Procedures for DI .......................................................................................... 3-2 
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3.3.3 
Follow-up Visit Testing Procedures for HT ........................................................................................ 3-2 
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3.4 
Non-study Visits ...................................................................................................................................... 3-2 
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3.5 
Initiating a New Treatment ...................................................................................................................... 3-2 
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CHAPTER 4: MISCELLANEOUS CONSIDERATIONS ............................................................................................ 4-1 
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4.1 
Contacts by the Jaeb Center for Health Research and Sites ..................................................................... 4-1 
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4.2 
Subject Withdrawals ................................................................................................................................ 4-1 
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4.3 
Management of Refractive Error .............................................................................................................. 4-1 
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4.4 
Risks ......................................................................................................................................................... 4-1 
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4.4.1 
Risks of Examination Procedures ........................................................................................................ 4-1 
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4.5 
Reporting of Adverse Events ................................................................................................................... 4-1 
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4.5.1 
Risk Assessment .................................................................................................................................. 4-1 
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4.6 
Discontinuation of Study .......................................................................................................................... 4-1 
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4.7 
Travel Reimbursement ............................................................................................................................. 4-1 
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4.8 
Study Costs .............................................................................................................................................. 4-2 
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4.9 
General Considerations ............................................................................................................................ 4-2 
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CHAPTER 5: SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS .................................................... 5-1 
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5.1 
Assessment of Investigator Interest / Recruitment Potential .................................................................... 5-1 
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5.2 
Sample Size .............................................................................................................................................. 5-1 
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5.3 
Primary Analysis – Symptom Success at One Year ................................................................................. 5-2 
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5.4 
Secondary Analysis – Motor Success at One Year .................................................................................. 5-3 
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5.5 
Additional Analyses ................................................................................................................................. 5-3 
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5.5.1 
Secondary Outcomes at One Year ....................................................................................................... 5-3 
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5.5.2 
Outcomes at 10 Weeks ........................................................................................................................ 5-3 
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CHAPTER 6: REFERENCES ......................................................................................................................................... 6-1 
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SAS1 Protocol v2.0 4-11-16 
1-1 
CHAPTER 1: BACKGROUND AND SUMMARY 
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This study is being conducted by the Pediatric Eye Disease Investigator Group (PEDIG) and is 
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funded through a cooperative agreement from the National Eye Institute. 
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1.1 
Background 
161 
Epidemiology and clinical characteristics: 
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New onset adult strabismus has been estimated to affect 54.1/100,000 in a recent population-
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based study in the USA.1  In this study, the most common types of new onset strabismus in 
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adults, after paralytic strabismus, were convergence insufficiency (8.4/100,000), small angle 
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hypertropia (7.5/100,000) and divergence insufficiency (6.0/100,000).  For each of these 
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types the incidence increased with increasing age.1 
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Convergence insufficiency: 
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Convergence insufficiency (CI) is characterized by an exodeviation greater at near than at 
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distance and a remote near point of convergence and/or decreased positive fusional vergence.2  
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It is typically associated with symptoms such as diplopia, eyestrain, asthenopia, frontal 
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headaches or problems reading.2-4  Treatment consists of either exercises,3, 4prisms,3, 4 surgery,4-
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6 or botulinum toxin injection.7 
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There is a paucity of evidence for the effectiveness of treatment for CI in adults, with most 
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previous reports studying effects in children.  A recent Cochrane review2 identified two 
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previous randomized clinical trials in adults.  Teitelbaum et al8 randomly assigned 29 
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presbyopic patients with symptomatic CI to either progressive addition lenses with base-in 
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prism or progressive addition lenses with no prism.  The authors concluded that base-in prism 
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glasses were effective in reducing the symptoms of CI, although interestingly, symptoms also 
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significantly improved with progressive addition lenses with no prism.8 Birnbaum et al9 
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randomly assigned 60 male adult patients to receive office-based vision therapy/orthoptics with 
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supplemental home therapy, home vision therapy alone, or no treatment.  Office vision therapy 
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with supplemental home therapy was reported to be most effective with a success rate of 62%.  
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Despite the findings of these two randomized trials there remains much uncertainty as to which 
186 
treatments are most effective for a given adult patient with CI and what are realistic success 
187 
rates. 
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189 
Divergence insufficiency: 
190 
Divergence insufficiency (DI) esotropia is a comitant esodeviation worse at distance fixation 
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than at near, typically associated with symptoms of diplopia at distance.10  Treatment most often 
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consists of either prism correction10-13 or strabismus surgery.14, 15  The established surgical 
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procedure for DI esotropia is lateral rectus resection.16-18  Nevertheless, in recent years bilateral 
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medial rectus recession has been advocated.14, 15, 19  There are few studies comparing treatments 
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for DI esotropia, and little data on treatment outcomes, especially over the long-term.  One recent 
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study19 claimed medial rectus recession was equivalent to lateral rectus resection but it was 
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retrospective, not randomized, and had small sample size (n=24) and therefore of insufficient 
198 
power to make such a determination. 
199 
 
200 
Hypertropia: 
201 
New onset small angle hypertropia (HT) in adults presents as a comitant hyperdeviation, 
202 
typically less than 10 prism diopters, in the absence of oblique muscle dysfunction.  The patient 
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SAS1 Protocol v2.0 4-11-16 
1-2 
typically experiences symptoms of vertical diplopia.  There are a range of possible causes for 
204 
such vertical misalignment including skew deviation, sagging eye syndrome,20 myotoxicity 
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following cataract surgery,21, 22 presumed micro-vascular event, or even central peripheral rivalry 
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(dragged fovea-diplopia syndrome).23-25  Treatment most often consists of prism correction of 
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diplopia or strabismus surgery, although partial occlusion may be used in cases of central 
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peripheral rivalry.  Regarding surgical approaches for small angle HT, some surgeons perform 
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superior rectus recession, while others have advocated mini-tenotomy (snip) procedures.26  There 
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are, however, limited data on the effectiveness of these treatments for small angle HT and few 
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studies, if any, comparing treatment outcomes.   
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Prospective Observational Studies: 
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A prospective observational study monitors different forms of treatment applied to patients with 
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a certain condition.  Individuals are enrolled in a prospective observational study on the basis of 
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either disease or exposure status.  The care provider, not a protocol, decides how a patient gets 
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treated.  Through direct data collection from care providers, the results of the ongoing disease 
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process and medical care can then be observed. 
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Prospective observational studies have the advantage of applying inclusion/exclusion criteria and 
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not dictating management.  The large patient sample often enables better estimation of outcome 
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rates.  Also, since data are collected within standard clinical practice, the results have high 
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external validity.  Weaknesses of observational studies include difficulty in identifying and 
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controlling all sources of bias, and challenges with respect to data analyses.  There may also be 
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variability in time intervals between visits and treatments, and the potential for confounding 
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makes treatment group comparisons difficult to interpret.  Despite these weaknesses, future 
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randomized controlled trials may be developed based on preliminary estimates of treatment 
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effects that an observational study provides for the studied conditions. 
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1.2 
Rationale for the study 
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Purpose of an adult CI-DI-HT strabismus prospective observational study: 
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A prospective adult strabismus observational study will provide data on the numbers, types and 
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clinical characteristics of adult patients with CI, DI or HT who are seen by PEDIG investigators 
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and are receiving certain types of treatments , and on the outcomes of those treatments over one 
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year.  These data will be used to generate hypotheses for possible future PEDIG studies, 
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including randomized trials.  Data collected will include angle of deviation, diplopia severity, 
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treatment type, and treatment outcome.   
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Public health importance: 
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There are limited prospective, standardized data available on adults with convergence 
241 
insufficiency, divergence insufficiency or small angle hypertropia, the commonest causes of non-
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paralytic adult strabismus.  This study will inform regarding the numbers and types of adults 
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with these conditions seen by PEDIG investigators, enabling the generation of hypotheses for 
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potential PEDIG studies and estimation of their recruitment feasibility. 
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1.3 
Considerations 
247 
It is recognized that estimates of treatment success may be biased by patient selection, but for 
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some conditions / treatments, these data will be the best available for planning future PEDIG 
249 
studies. 
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SAS1 Protocol v2.0 4-11-16 
1-3 
1.4 
Study Objectives 
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To describe clinical characteristics, treatments, and one-year outcomes of adults with 
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convergence insufficiency, divergence insufficiency, or small angle hypertropia.  Treatment 
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comparisons within the studied conditions will also be done to help develop future studies. 
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1.5 
Synopsis of Study Design 
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1.5.1 Synopsis of Study Design for CI 
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Major Eligibility Criteria (see section 2.2.1 for full details) 
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• Adults ≥18 years of age (adult onset of CI not required) 
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• No strabismus surgery in the past 10 years 
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• CI Symptom Survey score ≥21 points 
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• Near exodeviation of ≥4∆ and at least 4∆ larger than at distance by PACT 
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• Distance exodeviation ≤15∆ by PACT 
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• Vertical deviation ≤2∆ at distance and near by PACT 
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• No constant exotropia at distance or near 
266 
• Reduced positive fusional vergence (PFV) at near (<20∆ or fails Sheard’s criterion that the 
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PFV measures less than twice the magnitude of the near phoria) 
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• Near point of convergence (NPC) of ≥6 cm break 
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• No paralytic strabismus, paretic strabismus, restrictive strabismus, monocular diplopia, 
270 
thyroid eye disease, myasthenia gravis, chronic progressive external ophthalmoplegia, or eye 
271 
movement abnormalities associated with known neurological disease.  Patients with 
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Parkinson's disease can be enrolled if non-paretic deviation. 
273 
• Visual acuity 20/50 or better in both eyes by ETDRS or Snellen 
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• Ability to fuse with prism in space (see section 2.4.1) 
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• Investigator is initiating treatment with prism, orthoptic exercises,  botulinum toxin injection 
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or surgery 
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• If initiating treatment with botulinum toxin or surgery, planned injection or surgery to be 
278 
within 60 days of enrollment.  
279 
• Treatment to be initiated has not been used within the past one year 
280 
 
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Treatment 
282 
Treatment is per the investigator’s usual clinical practice. 
283 
 
284 
Data will be collected for the following treatment modalities:  
285 
• Bilateral medial rectus muscle resection surgery 
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• Single medial rectus muscle resection surgery 
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• Recess lateral rectus muscle resection medial rectus muscle surgery 
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• Bilateral lateral rectus muscle recession surgery 
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• Single lateral rectus muscle recession surgery 
290 
• Botulinum toxin injection 
291 
• Prisms 
292 
• Orthoptic exercises, including computer-based therapy 
293 
 
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Sample Size 
295 
50 subjects per non-surgical treatment modality (prism, orthoptic exercises) and up to 100 
296 
subjects undergoing surgery (maximum 50 per surgical modality) will be enrolled, for a total of 
297 

 
SAS1 Protocol v2.0 4-11-16 
1-4 
up to 200 subjects with CI. Recruitment will continue for 1 year, at which time the determination 
298 
will be made whether the recruitment period should be extended to allow for additional subjects 
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to be enrolled in treatment modality groups that have not reached their maximum.   
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Visit Schedule 
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• Baseline Visit 
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• 10 week ± 3 weeks following intervention  
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• 12-months ± 2 months following intervention 
305 
 
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Visits will be timed from the date of surgery or botulinum toxin injection (if applicable); or if 
307 
prescribed prism or orthoptic exercises, visits will be timed from the day of enrollment.  Subjects 
308 
can remain in the study up to an additional year and have up to two additional follow up visits if 
309 
their treatment modality is changed during the study. 
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Outcome 
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The primary outcome will be symptom success at the 10-week and 12-month visit, defined as 
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improvement of CI Symptom Survey (CISS) score of at least 9 points and an outcome score of 
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<21 points.  For surgical treatment, a secondary, motor outcome will evaluate how often subjects 
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have become orthotropic at distance and near after treatment. 
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SAS1 Protocol v2.0 4-11-16 
1-5 
Baseline Exam 
 
Confirm Eligibility as Defined in Section 2.2.1 
 
Testing Procedures 
• CI Symptom Survey (CISS) 
• Diplopia Questionnaire 
• Adult Strabismus 20 (AS-20) Questionnaire 
• Distance visual acuity (ETDRS or Snellen) 
• Ocular Alignment (cover/uncover, SPCT, PACT) 
• Fusion with prism in space 
• Positive fusional vergence 
• Near point of convergence 
1.5.2 Study Flow Chart: CI 
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Interim Outcome Exam: 10 weeks ± 3 weeks  
(timed from initiation of treatment) 
 
• CI Symptom Survey (CISS) 
• Diplopia Questionnaire 
• Adult Strabismus 20 (AS-20) Questionnaire 
• Distance visual acuity (ETDRS or Snellen: Same as at baseline) 
• Ocular Alignment (cover/uncover, SPCT, PACT) 
• Positive fusional vergence 
• Near point of convergence 
Outcome Exam: 12-Month ± 2 months exam 
(timed from initiation of treatment) 
 
• CI Symptom Survey (CISS) 
• Diplopia Questionnaire 
• Adult Strabismus 20 (AS-20) Questionnaire 
• Distance visual acuity (ETDRS or Snellen: Same as at baseline) 
• Ocular Alignment (cover/uncover, SPCT, PACT) 
• Positive fusional vergence 
• Near point of convergence 

 
SAS1 Protocol v2.0 4-11-16 
1-6 
1.5.3 Synopsis of Study Design for DI 
325 
Major Eligibility Criteria (see section 2.2.2 for full details) 
326 
• Adults ≥18 years of age  
327 
• Adult-onset DI (at ≥18 years of age) 
328 
• No prior strabismus surgery 
329 
• Symptoms of diplopia at distance with a frequency of sometimes or worse in primary 
330 
position  
331 
• 
Distance esodeviation of 2∆ to 30∆ and distance deviation is at least 1.25 times (25% larger 
332 
than) near deviation by PACT (i.e., maximum near deviation is at least 20% smaller than 
333 
distance deviation).  The distance deviation must exceed the near deviation by at least the 
334 
amounts provided in the table below. 
335 
 
336 
PACT Values for DI Eligibility  
337 
Distance 
Deviation 
2 
3 
4 
5 
6 
7 
8 
9 
10 12 14 16 18 20 25 30 
*Max Near 
Deviation 
1 
2 
3 
4 
4 
5 
6 
7 
8 
9 
10 12 14 16 20 20 
Calculation: Distance ≥ Near x 1.25 or Near ≤ Distance x 0.8 
338 
*Near deviation is the nearest study-permitted prism based on Strabismus Procedures Manual. 
339 
 
340 
• No more than 5∆ difference between right and left gaze by PACT 
341 
• No more than 10∆ difference between primary position and either upgaze or downgaze by 
342 
PACT  
343 
• Any coexisting vertical deviation must be less than the distance esodeviation and ≤10∆ by 
344 
PACT 
345 
• No paralytic strabismus, paretic strabismus, restrictive strabismus, monocular diplopia, 
346 
thyroid eye disease, myasthenia gravis, chronic progressive external ophthalmoplegia, or eye 
347 
movement abnormalities associated with known neurological disease.  Patients with 
348 
Parkinson's disease can be enrolled if non-paretic deviation 
349 
• Visual acuity 20/50 or better in both eyes by ETDRS or Snellen 
350 
• Ability to fuse with prism in space (see section 2.4.2) 
351 
• Investigator is initiating treatment with prism, orthoptic exercises, botulinum toxin injection, 
352 
or surgery 
353 
• If initiating treatment with botulinum toxin or surgery, planned injection or surgery to be 
354 
within 60 days of enrollment.  
355 
• Treatment to be initiated has not been used within the past one year  
356 
 
357 
Treatment 
358 
Treatment is per the investigator’s usual clinical practice. 
359 
 
360 
Data will be collected for the following treatment modalities:  
361 
• Bilateral lateral rectus muscle resection surgery 
362 
• Single lateral rectus muscle resection surgery 
363 
• Recess medial rectus muscle resection lateral rectus muscle surgery 
364 
• Bilateral medial rectus muscle recession surgery 
365 
• Single medial rectus muscle recession surgery 
366 
• Botulinum toxin injection 
367 

 
SAS1 Protocol v2.0 4-11-16 
1-7 
• Prisms 
368 
• Orthoptic exercises, including computer-based therapy 
369 
 
370 
Sample Size 
371 
50 subjects per non-surgical treatment modality (prism, orthoptic exercises) and up to 150 
372 
subjects undergoing surgery (maximum 50 per surgical modality) will be enrolled, for a total of 
373 
up to 250 subjects with DI.  Recruitment will continue for 1 year, at which time the 
374 
determination will be made whether the recruitment period should be extended to allow for 
375 
additional subjects to be enrolled in treatment modality groups that have not reached their 
376 
maximum.   
377 
 
378 
Visit Schedule 
379 
• Baseline Visit 
380 
• 10 week ± 3 weeks following intervention  
381 
• 12-months ± 2 months following intervention 
382 
 
383 
Visits will be timed from the date of surgery or botulinum toxin (if applicable); or if prescribed 
384 
prism or orthoptic exercises, visits will be timed from the day of enrollment.  Subjects can 
385 
remain in the study up to an additional year and have up to two additional follow up visits if their 
386 
treatment modality is changed during the study. 
387 
 
388 
Outcomes 
389 
The primary outcome will be symptom success at the 10-week and 12-month visit, defined as 
390 
diplopia “rarely” or “never” in primary position at distance on the diplopia questionnaire.  For 
391 
surgical treatment, a secondary, motor outcome will evaluate how often subjects have become 
392 
orthotropic at distance and near after treatment.  
393 
394 

 
SAS1 Protocol v2.0 4-11-16 
1-8 
 
Baseline Exam 
 
Confirm Eligibility as Defined in Section 2.2.2 
 
Testing Procedures 
• Diplopia Questionnaire 
• Adult Strabismus 20 (AS-20) Questionnaire 
• Distance visual acuity (ETDRS or Snellen) 
• Ocular Alignment (cover/uncover, SPCT, PACT) 
• Fusion with prism in space 
• Negative fusional vergence  
1.5.4 Study Flow Chart: DI 
395 
 
396 
 
 
397 
 
Interim Outcome Exam: 10 weeks ± 3 weeks 
(timed from initiation of treatment) 
• Diplopia Questionnaire 
• Adult Strabismus 20 (AS-20) Questionnaire 
• Distance visual acuity (ETDRS or Snellen: Same as at baseline) 
• Ocular Alignment (cover/uncover, SPCT, PACT) 
• Negative fusional vergence 
 
Outcome Exam: 12-Month ± 2 months exam 
(timed from initiation of treatment) 
• Diplopia Questionnaire 
• Adult Strabismus 20 (AS-20) Questionnaire 
• Distance visual acuity (ETDRS or Snellen: Same as at baseline) 
• Ocular Alignment (cover/uncover, SPCT, PACT) 
• Negative fusional vergence 

 
SAS1 Protocol v2.0 4-11-16 
1-9 
1.5.5 Synopsis of Study Design for HT 
398 
Major Eligibility Criteria (see section 2.2.3 for full details) 
399 
• Adults ≥18 years of age  
400 
• Adult-onset HT (at ≥18 years of age) 
401 
• No prior strabismus surgery 
402 
• Symptoms of diplopia at distance or near with a frequency of sometimes or worse in primary 
403 
position at distance or reading position 
404 
• Vertical deviation ≥1∆ to ≤10∆ at distance and near by prism and alternate cover test (PACT) 
405 
• No more than 4∆ difference from the primary in any gaze position by PACT 
406 
• Any coexisting esodeviation must be less than the vertical deviation by PACT 
407 
• Any coexisting exodeviation ≤10∆ by PACT  
408 
• No convergence insufficiency as defined in section 2.2.1 
409 
• No paralytic strabismus, paretic strabismus, restrictive strabismus, monocular diplopia, 
410 
thyroid eye disease, myasthenia gravis, chronic progressive external ophthalmoplegia, or eye 
411 
movement abnormalities associated with known neurological disease.  Patients with 
412 
Parkinson's disease can be enrolled if non-paretic deviation 
413 
• Visual acuity 20/50 or better in both eyes by ETDRS or Snellen 
414 
• Ability to fuse with prism in space (see section 2.4.3) 
415 
• Investigator is initiating treatment with prism, orthoptic exercises, botulinum toxin injection 
416 
or surgery 
417 
• If initiating treatment with botulinum toxin or surgery, planned injection or surgery to be 
418 
within 60 days of enrollment.  
419 
• Treatment to be initiated has not been used within the past one year  
420 
 
421 
Treatment 
422 
Treatment is per the investigator’s usual clinical practice. 
423 
 
424 
Data will be collected for the following treatment modalities:  
425 
• Vertical rectus muscle recession surgery 
426 
• Vertical rectus muscle mini-tenotomy (snip) surgery 
427 
• Botulinum toxin injection 
428 
• Prisms 
429 
• Orthoptic exercises, including computer-based therapy 
430 
 
431 
Sample Size 
432 
50 subjects per non-surgical treatment modality (prism, orthoptic exercises) and up to 100 
433 
subjects undergoing surgery (maximum 50 per surgical modality) will be enrolled, for a total of 
434 
up to 200 subjects with HT.  Recruitment will continue for 1 year, at which time the 
435 
determination will be made whether the recruitment period should be extended to allow for 
436 
additional subjects to be enrolled in treatment modality groups that have not reached their 
437 
maximum.   
438 
 
439 
Visit Schedule 
440 
• Baseline Visit 
441 
• 10-week ± 3 weeks following intervention  
442 
• 12-months ± 2 months following intervention 
443 
 
444 

 
SAS1 Protocol v2.0 4-11-16 
1-10 
Visits will be timed from the date of surgery or botulinum toxin injection (if applicable); or if 
445 
prescribed prism or orthoptic exercises, visits will be timed from the day of enrollment.  Subjects 
446 
can remain in the study up to an additional year and have up to two additional follow up visits if 
447 
their treatment modality is changed during the study. 
448 
 
449 
Outcomes 
450 
The primary outcome will be symptom success at the 10-week and 12-month visit, defined as 
451 
diplopia “rarely” or “never” both in primary position at distance and in reading position on the 
452 
diplopia questionnaire.  For surgical treatment, a secondary, motor outcome will evaluate how 
453 
often subjects have become orthotropic at distance and near after treatment. 
454 
 
455 
456 

 
SAS1 Protocol v2.0 4-11-16 
1-11 
 
Baseline Exam 
 
Confirm Eligibility as Defined in Section 2.2.3 
 
Testing Procedures 
• Diplopia Questionnaire 
• Adult Strabismus 20 (AS-20) Questionnaire 
• Distance visual acuity (ETDRS or Snellen) 
• Ocular Alignment (cover/uncover, SPCT, PACT) 
• Fusion with prism in space 
• Vertical fusional amplitudes 
• Double Maddox Rod Testing 
1.5.6 Study Flow Chart: HT 
457 
 
458 
 
459 
 
460 
 
461 
 
462 
 
 
463 
Interim Outcome Exam: 10 weeks ± 3 weeks 
(timed from initiation of treatment) 
• Diplopia Questionnaire 
• Adult Strabismus 20 (AS-20) Questionnaire 
• Distance visual acuity (ETDRS or Snellen: Same as at baseline) 
• Ocular Alignment (cover/uncover, SPCT, PACT) 
• Vertical fusional amplitudes 
• Double Maddox Rod Testing 
Outcome Exam: 12-Month ± 2 months exam 
(timed from initiation of treatment) 
 
• Diplopia Questionnaire 
• Adult Strabismus 20 (AS-20) Questionnaire 
• Distance visual acuity (ETDRS or Snellen: Same as at baseline) 
• Ocular Alignment (cover/uncover, SPCT, PACT) 
• Vertical fusional amplitudes 
• Double Maddox Rod Testing 

 
SAS1 Protocol v2.0 4-11-16 
2-12 
CHAPTER 2: SUBJECT ENROLLMENT 
464 
 
465 
2.1 
Eligibility Assessment and Informed Consent 
466 
A maximum of 650 subjects will be enrolled in the study.  A maximum of 50 subjects per 
467 
treatment modality (prism, orthoptic exercises, surgery of a specific type) per condition (CI, DI, 
468 
HT) will be enrolled, with up to 100 CI subjects treated with surgery, up to 150 DI subjects 
469 
treated with surgery, and up to 100 HT subjects treated with surgery.  Recruitment will continue 
470 
for 1 year, at which time the determination will be made whether the recruitment period should 
471 
be extended to allow for additional subjects to be enrolled in treatment modality groups that have 
472 
not reached their maximum.   
473 
 
474 
A subject is considered for the study after undergoing a routine eye examination (by a study 
475 
investigator as part of standard of care), or a referral, that identifies CI, DI, or HT that appears to 
476 
meet the eligibility criteria.  The study will be discussed with the subject.  Subjects who express 
477 
an interest in the study will be given a copy of the informed consent form to read.  Written 
478 
informed consent must be obtained from the subject prior to performing any study-specific 
479 
procedures that are not part of the subject’s routine care. 
480 
 
481 
 
482 
2.2 
Eligibility and Exclusion Criteria 
483 
2.2.1 Eligibility Criteria for CI 
484 
The following criteria must be met for the subject to be enrolled into the study: 
485 
• Adults ≥18 years of age (adult onset of CI not required) 
486 
• No strabismus surgery within the past 10 years 
487 
• CI Symptom Survey score ≥21 points 
488 
• Near exodeviation of ≥4∆ and at least 4∆ larger than at distance by PACT 
489 
• Distance exodeviation ≤15∆ by PACT 
490 
• Vertical deviation ≤2∆ at distance and near by PACT 
491 
• No constant exotropia at distance or near 
492 
• Reduced positive fusional vergence (PFV) at near (<20∆ or fails Sheard’s criterion that the 
493 
PFV measures less than twice the magnitude of the near phoria) 
494 
• Near point of convergence (NPC) of ≥6 cm break 
495 
• Visual acuity 20/50 or better in both eyes by ETDRS or Snellen 
496 
• No paralytic strabismus (e.g., 3rd, 4th, or 6th cranial nerve palsies, skew deviation, Duane 
497 
syndrome) 
498 
• No restrictive strabismus (e.g., blowout fracture, thyroid eye disease, post scleral buckle, 
499 
Brown syndrome) 
500 
• No monocular diplopia 
501 
• No paretic strabismus, thyroid eye disease, myasthenia gravis, chronic progressive external 
502 
ophthalmoplegia, or eye movement abnormalities associated with known neurological 
503 
disease.  Patients with Parkinson's disease can be enrolled if non-paretic deviation. 
504 
• No inferior or superior oblique overaction defined as 2+ or greater 
505 
• Ability to fuse with prism in space (see section 2.4.1) 
506 
• Ability to understand and complete a survey 
507 
• Investigator is initiating treatment with prism, orthoptic exercises, botulinum toxin injection 
508 
or surgery 
509 

 
SAS1 Protocol v2.0 4-11-16 
2-13 
• If initiating treatment with botulinum toxin or surgery, planned injection or surgery to be 
510 
within 60 days of enrollment  
511 
• Single treatment modality is planned (e.g., no combined prism and orthoptic exercises) 
512 
• Treatment to be initiated has not been used within the past one year  
513 
 
514 
2.2.2 Eligibility Criteria for DI 
515 
The following criteria must be met for the subject to be enrolled into the study: 
516 
• Adults ≥18 years of age 
517 
• Adult-onset DI (at ≥18 years of age) 
518 
• No prior strabismus surgery  
519 
• Symptoms of diplopia at distance with a frequency of sometimes or worse in primary 
520 
position (in current glasses if wearing glasses) 
521 
• Distance esodeviation of 2∆ to 30∆ and distance deviation is at least 1.25 times (25% larger 
522 
than) near deviation by PACT (i.e., maximum near deviation is at least 20% smaller than 
523 
distance deviation). The distance deviation must exceed the near deviation by at least the 
524 
amounts provided in the table below. 
525 
 
526 
PACT Values for DI Eligibility  
527 
Distance 
Deviation 
2 
3 
4 
5 
6 
7 
8 
9 
10 12 14 16 18 20 25 30 
*Max Near 
Deviation 
1 
2 
3 
4 
4 
5 
6 
7 
8 
9 
10 12 14 16 20 20 
Calculation: Distance ≥ Near x 1.25 or Near ≤ Distance x 0.8 
528 
*Near deviation is the nearest study-permitted prism based on Strabismus Procedures Manual. 
529 
 
530 
• No more than 5∆ difference between right and left gaze by PACT 
531 
• No more than 10∆ difference between the primary position at distance and either upgaze or 
532 
downgaze ≤10∆ by PACT 
533 
• Any coexisting vertical deviation must be less than distance esodeviation and ≤10∆ by PACT 
534 
• Visual acuity 20/50 or better in both eyes by ETDRS or Snellen 
535 
• No paralytic strabismus (e.g., 3rd, 4th, or 6th cranial nerve palsies, skew deviation, Duane 
536 
syndrome) 
537 
• No restrictive strabismus (e.g., blowout fracture, thyroid eye disease, post scleral buckle, 
538 
Brown syndrome) 
539 
• No monocular diplopia 
540 
• No paretic strabismus, thyroid eye disease, myasthenia gravis, chronic progressive external 
541 
ophthalmoplegia, or eye movement abnormalities associated with known neurological 
542 
disease.  Patients with Parkinson's disease can be enrolled if non-paretic deviation 
543 
• No inferior or superior oblique overaction defined as 2+ or greater 
544 
• Ability to fuse with prism in space (see section 2.4.2) 
545 
• Ability to understand and complete a survey  
546 
• Investigator is initiating treatment with prism, orthoptic exercises, botulinum toxin injection 
547 
or surgery 
548 
• If initiating treatment with botulinum toxin or surgery, planned injection or surgery to be 
549 
within 60 days of enrollment  
550 
• Single treatment modality planned (e.g., no combined prism and orthoptic exercises) 
551 
• Treatment to be initiated has not been used within the past one year  
552 

 
SAS1 Protocol v2.0 4-11-16 
2-14 
 
553 
2.2.3 Eligibility Criteria for HT 
554 
The following criteria must be met for the subject to be enrolled into the study: 
555 
• Adults ≥18 years of age 
556 
• Adult-onset HT (at ≥18 years of age) 
557 
• No prior strabismus surgery  
558 
• Symptoms of diplopia at distance or near with a frequency of sometimes or worse in primary 
559 
or reading position (in current glasses if wearing glasses) 
560 
• Vertical deviation ≥1∆ to ≤10∆ at distance and near by PACT 
561 
• No more than 4∆ difference from the primary in any gaze position by PACT 
562 
• Any coexisting esodeviation must be less than the vertical deviation 
563 
• Any coexisting exodeviation ≤10∆ by PACT 
564 
• No convergence insufficiency as defined in section 2.2.1 
565 
• Visual acuity 20/50 or better in both eyes by ETDRS or Snellen 
566 
• No paralytic strabismus (e.g., 3rd, 4th, or 6th cranial nerve palsies, skew deviation, Duane 
567 
syndrome) 
568 
• No restrictive strabismus (e.g., blowout fracture, thyroid eye disease, post scleral buckle, 
569 
Brown syndrome) 
570 
• No monocular diplopia 
571 
• No paretic strabismus, thyroid eye disease, myasthenia gravis, chronic progressive external 
572 
ophthalmoplegia, or eye movement abnormalities associated with known neurological 
573 
disease.  Patients with Parkinson's disease can be enrolled if non-paretic deviation. 
574 
• No inferior or superior oblique overaction defined as 2+ or greater 
575 
• Ability to fuse with prism in space (see section 2.4.3) 
576 
• Ability to understand and complete a survey  
577 
• Investigator is initiating treatment with prism, orthoptic exercises,  botulinum toxin injection 
578 
or surgery 
579 
• If initiating treatment with botulinum toxin or surgery, planned injection or surgery to be 
580 
within 60 days of enrollment  
581 
• Single treatment modality planned (e.g., no combined prism and orthoptic exercises) 
582 
• Treatment to be initiated has not been used within the past one year  
583 
 584 
2.3 
Historical Information 
585 
Historical information collected at enrollment will include the following: 
586 
• Presence of co-existing neurological conditions (e.g., Parkinson’s, Progressive supranuclear 
587 
palsy, basal ganglia disease, stroke, or intracranial tumor) and any treatment 
588 
• Presence of epiretinal membrane, age-related macular degeneration (dry or neovascular), or 
589 
macular pathology (if known) 
590 
• Heart disease 
591 
• Diabetes 
592 
• Autoimmune disease (other than myasthenia gravis and thyroid eye disease) 
593 
• Previous treatment for strabismus (surgical and/or non-surgical) 
594 
• Other major medical problems (e.g., significant head trauma) 
595 
 
596 

 
SAS1 Protocol v2.0 4-11-16 
2-15 
2.4 
Procedures at the Enrollment Visit 
597 
All examination procedures must be tested before initiating planned treatment and within 7 days 
598 
of enrollment.  All examination procedures at enrollment are performed in the subject’s current 
599 
correction, if required, and without cycloplegia.  Any subjects wearing pre-study prism 
600 
correction will be measured in trial frames without prism (unless otherwise noted below).  If new 
601 
correction is prescribed on the day of testing, or if the subject forgot to bring his/her spectacles, 
602 
then testing should be done in trial frames.  Full details for each procedure are listed in the 
603 
Procedures Manual.   
604 
 
605 
2.4.1 Enrollment Procedures for CI 
606 
 
607 
1. Convergence Insufficiency Symptom Survey (CISS) 
608 
 
609 
2. Diplopia Questionnaire (DQ) 
610 
 
611 
3. Adult Strabismus 20 (AS-20) Questionnaire 
612 
 
613 
4. Distance Visual Acuity 
614 
▪ 
Monocular distance visual acuity testing will be performed in each eye using 
615 
ETDRS or Snellen optotypes.  
616 
▪ 
If wearing ground-in prism correction, testing will be done wearing current 
617 
correction with prism; if wearing Fresnel prism, testing will be done in trial 
618 
frames without prism correction.   
619 
 
620 
The following must be tested by an examiner who is a pediatric ophthalmologist, 
621 
pediatric optometrist, or certified orthoptist. 
622 
 
623 
5. Ocular Alignment Testing 
624 
▪ 
Ocular alignment will be assessed by the cover/uncover test and by simultaneous 
625 
prism and cover test (SPCT) in primary gaze position at distance (6 meters) and at 
626 
near (1/3 meter).   
627 
▪ 
Prism and alternate cover test (PACT) will be tested at distance (6 meters) and 
628 
near (1/3 meter) in primary position. 
629 
 
630 
6. Fusion with Prism in Space 
631 
▪ 
Ability to fuse with prism in space will be determined by asking the subject to 
632 
view a 20/50 single optotype at 6 meters while neutralizing the deviation with free 
633 
prisms.  Subjects should be asked if they can make the image single.  Subjects 
634 
who are unable to make the image single are ineligible.    
635 
 
636 
7. Positive Fusional Vergence (PFV)  
637 
▪ 
PFV will be measured with a horizontal prism bar and a hand-held fixation target 
638 
(20/50 single optotype) at 40 cm.  Blur, break, and recovery points will be 
639 
recorded.  If no blur point is detected, the PFV score will be the break point 
640 
measurement.  
641 
 
642 
8. Near Point of Convergence (NPC) 
643 
▪ 
Break and recovery values will be measured.   
644 

 
SAS1 Protocol v2.0 4-11-16 
2-16 
 
645 
2.4.2 Enrollment Procedures for DI 
646 
 
647 
1. Diplopia Questionnaire 
648 
 
649 
2. Adult Strabismus 20 (AS-20) Questionnaire 
650 
 
651 
3. Distance Visual Acuity 
652 
▪ 
Monocular distance visual acuity testing will be performed in each eye using 
653 
ETDRS or Snellen optotypes.  
654 
▪ 
If wearing ground-in prism correction, testing will be done wearing current 
655 
correction with prism; if wearing Fresnel prism, testing will be done in trial 
656 
frames without prism correction.   
657 
 
658 
The following must be tested by an examiner who is a pediatric ophthalmologist, 
659 
pediatric optometrist, or certified orthoptist. 
660 
 
661 
4. Ocular Alignment Testing 
662 
▪ 
Ocular alignment will be assessed by the cover/uncover test and by simultaneous 
663 
prism and cover test (SPCT) in primary gaze position at distance (6 meters) and at 
664 
near (1/3 meter).  
665 
▪ 
Prism and alternate cover test (PACT) will be tested at distance (6 meters) and 
666 
near (1/3 meter) in primary position. 
667 
 
668 
5. Fusion with Prism in Space 
669 
▪ 
Ability to fuse with prism will be determined by asking the subject to view a 
670 
20/50 single optotype at 6 meters, and using prism(s), determine if any 
671 
combination allows the subject to have single vision.  Subjects who are unable to 
672 
make the image single are ineligible.  
673 
 
674 
6. Negative Fusional Vergence (NFV) 
675 
▪ 
NFV will be measured with a horizontal prism bar while the subject is viewing an 
676 
accommodative target (20/50 single optotype) at 6 meters.  Blur, break, and 
677 
recovery points will be recorded.  If no blur point is measured, the NFV score will 
678 
be the break point measurement.  
679 
 
680 
2.4.3 Enrollment Procedures for HT 
681 
 
682 
1. Diplopia Questionnaire 
683 
 
684 
2. Adult Strabismus 20 (AS-20) Questionnaire 
685 
 
686 
3. Distance Visual Acuity 
687 
▪ 
Monocular distance visual acuity testing will be performed in each eye using 
688 
ETDRS or Snellen optotypes.  
689 
▪ 
If wearing ground-in prism correction, testing will be done wearing current 
690 
correction with prism; if wearing Fresnel prism, testing will be done in trial 
691 
frames without prism correction.   
692 

 
SAS1 Protocol v2.0 4-11-16 
2-17 
 
693 
The following must be tested by an examiner who is a pediatric ophthalmologist, 
694 
pediatric optometrist, or certified orthoptist. 
695 
 
696 
4. Ocular Alignment Testing 
697 
▪ 
Ocular alignment will be assessed by the cover/uncover test and by simultaneous 
698 
prism and cover test (SPCT) in primary gaze position at distance (6 meters) and at 
699 
near (1/3 meter).  
700 
▪ 
Prism and alternate cover test (PACT) will be tested at distance (6 meters) and 
701 
near (1/3 meter) in primary position. 
702 
 
703 
5. Fusion with Prism in Space 
704 
▪ 
Ability to fuse with prism will be determined by asking the subject to view a 
705 
20/50 single optotype at 6 meters, and using prism(s), determine if any 
706 
combination allows the subject to have single vision.  Subjects who are unable to 
707 
make the image single are ineligible.  
708 
 
709 
6. Vertical Fusional Amplitudes 
710 
▪ 
Vertical fusional amplitudes will be measured with a vertical prism bar while the 
711 
subject is viewing an accommodative target (20/50 single optotype) at 6 meters.  
712 
Break and recovery points will be recorded.  Measurements will be taken in both 
713 
vertical directions to measure the range of vertical fusion.   
714 
▪ 
Vertical deviation should be corrected at least with sufficient prism to give the 
715 
subject single vision either in current correction (if pre-study prism) or with prism 
716 
correction in trial frames.   
717 
 
718 
7. Double Maddox Rod Testing 
719 
▪ 
Ocular cyclotorsion will be assessed by double Maddox rod in primary gaze 
720 
position at near (1/3 meters).   
721 
 
722 

 
SAS1 Protocol v2.0 4-11-16 
3-1 
CHAPTER 3: TREATMENT AND FOLLOW-UP 
723 
 
724 
3.1 
Treatment 
725 
Treatment is at investigator discretion and may be changed or discontinued at any time during 
726 
the study.  The type of treatment and other treatment details (e.g., magnitude of prism, amount of 
727 
orthoptic exercises) will be recorded at the time of enrollment when the treatment is prescribed.  
728 
For surgical subjects, the type and amount of surgery will be recorded.  If an adjustable 
729 
technique is used, the final location of the muscle and alignment after adjustment will be 
730 
recorded.  For those treated with botulinum toxin injection, the muscle(s) injected and dose will 
731 
be recorded.  The timing of surgical intervention after enrollment is at investigator discretion; 
732 
however, the enrollment assessments must be redone if surgery is not done within 60 days.  
733 
 
734 
Changing treatment within a modality (e.g., frequency, strength, intensity) has no impact on the 
735 
subject’s visit schedule.  Switching to a different treatment or adding a second treatment to the 
736 
initial treatment has implications for the subject’s visit schedule (see section 3.5). 
737 
 
738 
3.2 
Visit Schedule 
739 
Subjects enrolled will have visits at the following times: 
740 
• 10 weeks ± 3 weeks following intervention 
741 
• 12 months ± 2 months following intervention 
742 
 
743 
Visits will be timed from the date of surgery or botulinum toxin injection (if applicable); or if 
744 
prescribed prism or orthoptic exercises, will be timed from the day of enrollment.  If a new 
745 
treatment is initiated, the visit schedule may restart or the subject’s study participation may end, 
746 
according to the details in section 3.5. 
747 
 
748 
3.3 
Follow-up Visit Testing Procedures (10-week and 12-month visits) 
749 
At each visit, data on treatments received, any change in the amount/intensity of treatment, or 
750 
any major change in eye condition since the last visit will be collected.  In addition, the 
751 
following will be performed / completed as done at the enrollment exam in the subject’s current 
752 
correction, if required, and without cycloplegia.  Questionnaires and the symptom survey (if 
753 
applicable) should be administered to the subject prior to other examination procedures.  Any 
754 
subjects wearing prism correction will be measured in trial frames without prism (unless 
755 
otherwise noted below).  If new correction is prescribed on the day of testing, or if the subject 
756 
forgot to bring his/her spectacles, then testing should be done in trial frames.      
757 
 
758 
3.3.1 Follow-up Visit Testing Procedures for CI 
759 
See section 2.4.1 for details. 
760 
1. CISS 
761 
2. Diplopia Questionnaire 
762 
3. AS-20 Questionnaire 
763 
4. Distance Visual Acuity 
764 
• If wearing ground-in prism correction, testing will be done wearing current correction 
765 
with prism; if wearing Fresnel prism, testing will be done in trial frames without 
766 
prism correction.   
767 
5. Ocular Alignment Testing 
768 
6. Positive Fusional Vergence 
769 

 
SAS1 Protocol v2.0 4-11-16 
3-2 
7. Near Point of Convergence 
770 
 
771 
3.3.2 Follow-up Visit Testing Procedures for DI 
772 
See section 2.4.2 for details. 
773 
1. Diplopia Questionnaire 
774 
2. AS-20 Questionnaire 
775 
3. Distance Visual Acuity 
776 
• If wearing ground-in prism correction, testing will be done wearing current correction 
777 
with prism; if wearing Fresnel prism, testing will be done in trial frames without 
778 
prism correction.   
779 
4. Ocular Alignment Testing 
780 
5. Negative Fusional Vergence 
781 
 
782 
3.3.3 Follow-up Visit Testing Procedures for HT 
783 
See section 2.4.3 for details. 
784 
1. Diplopia Questionnaire 
785 
2. AS-20 Questionnaire 
786 
3. Distance Visual Acuity 
787 
• If wearing ground-in prism correction, testing will be done wearing current correction 
788 
with prism; if wearing Fresnel prism, testing will be done in trial frames without 
789 
prism correction.   
790 
4. Ocular Alignment Testing 
791 
5. Vertical Fusional Amplitudes 
792 
• Vertical deviation should be corrected at least with sufficient prism to give the subject 
793 
single vision either in current correction (if pre-study prism) or with prism correction 
794 
in trial frames.   
795 
6. Double Maddox Rod Testing 
796 
 
797 
3.4 
Non-study Visits  
798 
Additional non-study visits and treatment are at investigator discretion.  Investigators must 
799 
follow the procedures for initiating a new treatment during the study as outlined in section 3.5.  
800 
 
801 
3.5 
Initiating a New Treatment 
802 
If any new treatment is initiated during the study an early outcome exam as outlined in section 
803 
3.3 will be completed.  Study participation will end if the new treatment is prism or exercises, 
804 
unless initially enrolled in the surgery or botox injection group.  If the new treatment is a new 
805 
surgical modality or botox injection (not a re-operation or re-injection in the study), the 
806 
examination will serve both as the outcome exam for the initial treatment and the baseline exam 
807 
for the newly initiated surgery or botox injection, if the subject still meets eligibility criteria.  The 
808 
subject will then be followed for an additional 12-months in the study in the new treatment, as if 
809 
they had been newly enrolled.   
810 
 
811 
In the event that the study category for the newly initiated surgical modality is no longer 
812 
recruiting subjects, the subject will complete an early outcome exam at the time the new surgery 
813 
or botox injection is prescribed and study participation will end for this subject. 
814 
 
815 

 
SAS1 Protocol v2.0 4-11-16 
3-3 
Subjects who have had surgery or botox injection as their initial treatment (or as a new treatment 
816 
during the study) will continue to be followed until the 12-month outcome exam whether or not 
817 
an additional treatment is initiated.  The exception is if a re-operation or re-injection is planned 
818 
prior to the 12-month outcome.  In this case, an early outcome exam will be completed at the 
819 
time surgery is prescribed.  Study participation will end following the outcome examination.  
820 
 
821 
Subjects who have completed the study and are returning for additional treatment following an 
822 
unspecified period of time beyond the outcome exam may be enrolled a second time provided 
823 
they meet eligibility criteria and the study category for the newly initiated treatment is still 
824 
recruiting subjects.  Subjects enrolling as a study subject a second time must repeat the consent 
825 
process.  
826 
 
827 

 
SAS1 Protocol v2.0 4-11-16 
4-1 
CHAPTER 4: MISCELLANEOUS CONSIDERATIONS 
828 
 
829 
4.1 
Contacts by the Jaeb Center for Health Research and Sites 
830 
The Jaeb Center serves as the PEDIG Coordinating Center.  The Jaeb Center will be provided 
831 
with the subject’s contact information.  The Jaeb Center will contact each subject one month 
832 
before any 12-month visit (including a second 12-month visit which could be required if the 
833 
patient changed treatments during the study).  Permission for such contacts will be included in 
834 
the Informed Consent Form.  The principal purpose of the contacts will be to help coordinate 
835 
scheduling of the 12-month outcome examination.   
836 
 
837 
4.2 
Subject Withdrawals 
838 
Subjects may withdraw from the study at any time.  This is expected to be a very infrequent 
839 
occurrence in view of the study design’s similarity to routine clinical practice.  If the subject 
840 
indicates they want to withdraw from the study, the investigator personally should attempt to 
841 
speak with them to determine the reason.  If their interest is in transferring their care to another 
842 
eye care provider, every effort should be made to comply with this and at the same time try to 
843 
keep the participant in the study under the new provider’s care. 
844 
 
845 
4.3 
Management of Refractive Error 
846 
Management of refractive error is at the discretion of the investigator.    
847 
 
848 
4.4 
Risks 
849 
There are no risks in this study that would not be part of usual care. 
850 
 
851 
4.4.1 Risks of Examination Procedures 
852 
The procedures in this study are part of daily eye care practice in the United States and pose no 
853 
known risks.  
854 
 
855 
4.5 
Reporting of Adverse Events 
856 
No treatments are being prescribed that are not part of usual care.  Investigators will abide by 
857 
local IRB reporting requirements. 
858 
 
859 
4.5.1 Risk Assessment  
860 
It is the investigators’ opinion that the protocol’s level of risk is research not involving greater 
861 
than minimal risk.  
862 
 
863 
4.6 
Discontinuation of Study 
864 
The study may be discontinued by the Steering Committee (with approval of the Data and Safety 
865 
Monitoring Committee) prior to the preplanned completion of enrollment and follow-up for all 
866 
subjects. 
867 
 
868 
4.7 
Travel Reimbursement 
869 
Subjects will be compensated $25 for each 10-week visit and $50 for each 12-month visit (by 
870 
money-card) up to a maximum of $150.  If there are extenuating circumstances, and the subject 
871 

 
SAS1 Protocol v2.0 4-11-16 
4-2 
is unable to complete study visits without additional funds for travel costs, additional funds may 
872 
be provided. 
873 
 
874 
4.8 
Study Costs  
875 
The study will pay for visits specific to the research study, but will not pay for usual care visits 
876 
that would occur whether or not the subject was in the study.  The cost of usual care visits will be 
877 
the responsibility of the participant or his/her insurance company.  
878 
 
879 
Any costs associated with treatment will not be paid for by the study and will be the 
880 
responsibility of the participant or his/her insurance company.  
881 
 
882 
4.9 
General Considerations 
883 
The study is being conducted in compliance with the policies described in the network policies 
884 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
885 
the protocol described herein, and with the standards of Good Clinical Practice. 
886 
 
887 
Data will be directly collected in electronic case report forms, which will be considered the 
888 
source data.   
889 
 
890 
There is no restriction on the number of participants to be enrolled by a site.  A risk-based 
891 
monitoring approach will be followed, consistent with the FDA “Guidance for Industry 
892 
Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring” (August 2013). 
893 

 
SAS1 Protocol v2.0 4-11-16 
5-1 
CHAPTER 5: SAMPLE SIZE ESTIMATION AND STATISTICAL ANALYSIS 
894 
 
895 
5.1 
Assessment of Investigator Interest / Recruitment Potential 
896 
At the February 2014 PEDIG Study Group meeting, 18 (44%) of 41 ophthalmologist 
897 
investigators and 26 (65%) of 40 optometrists investigators indicated they would be willing to 
898 
participate in this study.  In addition, 8 (20%) of 41 ophthalmologists and 8 (20%) of 40 
899 
optometrists rated this protocol in the top 5 of 18 protocol ideas reviewed with the group.  The 
900 
study ranked 13th among the 18 protocol ideas reviewed with the group for the 81 investigators 
901 
overall. 
902 
 
903 
Table 1 shows a summary of the results from a February 2015 email survey of PEDIG 
904 
investigators.  For each condition (CI, DI, and HT), investigators were asked whether they 
905 
treated patients with the condition and how many they treated with various treatment modalities 
906 
over the course of one year.   
907 
 
908 
Table 1: Assessment of Recruitment Potential  
909 
 
Condition  
Number of Patients Treated in One Year In PEDIG Network* 
Prism 
Orthoptic Exercises 
Surgery 
CI 
229 
192 
  23** 
DI 
119 
20 
    85*** 
HT 
194 
10 
     39**** 
* Cases treated with more than one type of treatment are counted for each type of treatment. 
910 
** Bilateral medial rectus resection (N=11), other (N=12)  
911 
*** Bilateral medial rectus recession (N=51), bilateral lateral rectus resection (N=13), other (N=21)  
912 
****Vertical rectus recession (N=37), other (N=2)  
913 
 
914 
5.2 
Sample Size  
915 
The maximum total sample size of 650 is based on a convenience sample of a maximum of 50 
916 
subjects per treatment modality (prism, orthoptic exercises, surgery of a specific type) per 
917 
condition (CI, DI, HT), with up to 100 subjects treated with surgery for CI and for HT, and up to 
918 
150 subjects treated with surgery for DI (Table 2). 
919 
 
920 
Table 2: Maximum Sample Size for Each Condition/ Treatment Modality 
921 
 
Condition  
Maximum Sample Size  
Prism 
Orthoptic Exercises 
Surgery 
CI 
50 
50 
100* 
DI 
50 
50 
150* 
HT 
50 
50 
100* 
*Within this limit for the total number of surgeries for a given condition, no more than 50 surgeries of a specific 
922 
type (e.g. bilateral medial rectus recessions, bilateral lateral rectus resection, botulinum toxin injection, etc.) may be 
923 
enrolled. 
924 
 
925 
Based on the assessment of recruitment potential (section 5.1), about half of the 
926 
modality/condition groups would be expected to be filled to 50 subjects within one year (see 
927 
Table 1).  The remaining modality/condition groups might have a smaller-than-desired sample 
928 
size for analysis or might require recruitment for more than one year.   
929 
 
930 
931 

 
SAS1 Protocol v2.0 4-11-16 
5-2 
Table 3 shows the expected half-widths for the 95% confidence interval for the success 
932 
proportion estimate for each modality/condition group.   
933 
 
934 
Table 3: Expected ½-Width of 95% Confidence Interval as a Function of Sample Size and 
935 
Success Proportion* 
936 
 
One-Year  
Success Proportion  
Sample Size 
 
10 
 
20 
 
30  
 
40 
 
50  
1% 
6% 
4% 
4% 
3% 
3% 
3% 
11% 
8% 
6% 
5% 
5% 
5% 
14% 
10% 
8% 
7% 
6% 
10% 
19% 
13% 
11% 
9% 
8% 
15% 
22% 
16% 
13% 
11% 
10% 
20% 
25% 
18% 
14% 
12% 
11% 
25% 
27% 
19% 
16% 
13% 
12% 
30% 
28% 
20% 
16% 
14% 
13% 
40% 
30% 
22% 
18% 
15% 
14% 
50% 
31% 
22% 
18% 
15% 
14% 
*Note: The grey boxes indicate that validity of confidence interval widths is questionable because the normal 
937 
approximation might not be valid given these low probability of success and/or small sample sizes.   
938 
 
939 
After accounting for up to 5% loss to follow-up, a sample size of 50 patients per treatment 
940 
modality (prism, orthoptic exercises, surgery of a specific type) per condition would contribute 
941 
about 47 subjects to the point estimate for a dichotomous success/failure outcome at one year. 
942 
With 47 subjects, the maximum width of the resulting confidence intervals on each point 
943 
estimate would be ±14%.   
944 
 
945 
5.3 
Primary Analysis – Symptom Success at One Year 
946 
For each of the modality/condition groups, the primary analysis will be an estimation of the 
947 
proportion of patients of patients with treatment success based on improvement of symptoms at 
948 
10 weeks post intervention and at one year, with 95% confidence intervals. 
949 
 
950 
Table 4 shows the criteria for symptom success for each condition, which will be used to assess 
951 
all treatment modalities.    
952 
 
953 
Table 4: One-Year Symptom Success Criteria for Each Condition 
954 
Condition 
One-Year Symptom Success Criteria 
CI 
improvement of CI Symptom Survey (CISS) score of at least 9 points AND a 
score of <21 points   
DI 
diplopia no more than rarely in the past week in the primary position (question 
#1.1 on the Diplopia questionnaire)  
HT  
diplopia no more than rarely in the past week both in the primary position and 
for reading (questions #1.1 and #1.2 on the Diplopia questionnaire) 
 
955 
For patients who initiate a new treatment before completing one year of follow-up, the symptom 
956 
success/failure status from the visit at which treatment was changed (i.e., the 10-week interim 
957 
visit or an early outcome visit) will be brought forward as their one-year outcome. 
958 
 
959 

 
SAS1 Protocol v2.0 4-11-16 
5-3 
Rubin’s multiple imputation21 will be used to impute outcome for patients who have not changed 
960 
treatments  but who are who are lost to follow-up or withdraw from the study prior to one-year 
961 
exam.   
962 
 
963 
5.4 
Secondary Analysis – Motor Success at One Year 
964 
For each surgery type within a condition, a secondary objective will be to calculate the 
965 
proportion of patients with motor success at one year and a 95% confidence interval.  Motor 
966 
success will be defined as orthotropia by cover/uncover at distance and near fixation in primary 
967 
position at one year.  Similar to the primary analysis of symptom success, for patients who 
968 
change treatments before completing one year of follow-up, the motor success/failure status from 
969 
the visit at which treatment was changed (i.e., the 10-week interim visit or an early outcome 
970 
visit) will be brought forward as the one-year outcome.  In addition, Rubin’s multiple 
971 
imputation21 will be used to impute outcome for patients who have not changed treatments but 
972 
who are who are lost to follow-up or withdraw from the study prior to one-year exam. 
973 
 
974 
5.5 
Additional Analyses  
975 
5.5.1 Secondary Outcomes at One Year  
976 
Secondary outcomes at one year will be evaluated within each modality/condition.  Secondary 
977 
outcomes to be assessed include motor alignment, near point of convergence (CI only), positive 
978 
fusional vergence (CI only), negative fusional vergence (DI only), vertical fusional vergence (HT 
979 
only), and the Adult Strabismus 20 (AS-20) questionnaire.  In addition, mean CI Symptom 
980 
Survey (CISS) score will be evaluated for CI, and the AS-20 and Diplopia Questionnaire will be 
981 
evaluated as a continuous outcomes for all three conditions.  
982 
 
983 
5.5.2 Outcomes at 10 Weeks 
984 
Outcomes at the 10-week interim visit will be evaluated similarly to the primary and secondary 
985 
analyses defined for one-year time points (sections 5.3, 5.4 and 5.5.1).   
986 
 
987 
 
988 

 
SAS1 Protocol v2.0 4-11-16 
6-1 
CHAPTER 6: REFERENCES 
989 
 
990 
1. Martinez-Thompson JM, Diehl NN, Holmes JM, Mohney BG. Incidence, types, and lifetime 
991 
risk of adult-onset strabismus. Ophthalmology 2014;121:877-882. 
992 
2. Scheiman M, Gwiazda J, Li T. Non-surgical interventions for convergence insufficiency. 
993 
Cochrane Database of Systematic Reviews 2011;16:CD006768. 
994 
3. Lavrich JB. Convergence insufficiency and its current treatment. Current Opinion in 
995 
Ophthalmology 2010;21:356-360. 
996 
4. Cooper J, Jamal N. Convergence insufficiency-a major review. Optometry 2012;83:137-158. 
997 
5. von Noorden GK. Resection of both medial rectus muscles in organic convergence 
998 
insufficiency. American Journal of Ophthalmology 1976;81:223-226. 
999 
6. Choi DG, Rosenbaum AL. Medial rectus resection(s) with adjustable suture for intermittent 
1000 
exotropia of the convergence insufficiency type. Journal of AAPOS: American Association 
1001 
for Pediatric Ophthalmology & Strabismus 2001;5:13-17. 
1002 
7. Saunte JP, Holmes JM. Sustained improvement of reading symptoms following botulinum 
1003 
toxin A injection for convergence insufficiency. Strabismus 2014;22:95-99. 
1004 
8. Teitelbaum B, Pang Y, Krall J. Effectiveness of base in prism for presbyopes with 
1005 
convergence insufficiency. Optometry and Vision Science 2009;86:153-156. 
1006 
9. Birnbaum MH, Soden R, Cohen AH. Efficacy of vision therapy for convergence 
1007 
insufficiency in an adult male population. Journal of the American Optometric Association 
1008 
1999;70:225-232. 
1009 
10. Scheiman M, Gallaway M, Ciner E. Divergence insufficiency: characteristics, diagnosis, and 
1010 
treatment. American Journal of Optometry & Physiological Optics 1986;63:425-431. 
1011 
11. Tamhankar MA, Ying GS, Volpe NJ. Effectiveness of prisms in the management of diplopia 
1012 
in patients due to diverse etiologies. Journal of Pediatric Ophthalmology and Strabismus 
1013 
2012;49:222-228. 
1014 
12. Prangen Ade H, Koch FL. Divergence Insufficiency: A Clinical Study. Transactions of the 
1015 
American Ophthalmological Society 1937;35:136-148. 
1016 
13. Godts D, Mathysen DG. Distance esotropia in the elderly. British Journal of Ophthalmology 
1017 
2013;97:1415-1419. 
1018 
14. Thomas AH. Divergence insufficiency. Journal of AAPOS: American Association for 
1019 
Pediatric Ophthalmology & Strabismus 2000;4:359-361. 
1020 
15. Bothun ED, Archer SM. Bilateral medial rectus muscle recession for divergence 
1021 
insufficiency pattern esotropia. Journal of AAPOS: American Association for Pediatric 
1022 
Ophthalmology & Strabismus 2005;9:3-6. 
1023 
16. Wiggins RE, Jr., Baumgartner S. Diagnosis and management of divergence weakness in 
1024 
adults. Ophthalmology 1999;106:1353-1356. 
1025 
17. Simpson GV. Primary divergence insufficiency. Transactions of the American 
1026 
Ophthalmological Society 1973;71:152-161; discussions 161-152. 
1027 
18. Stager DR, Sr., Black T, Felius J. Unilateral lateral rectus resection for horizontal diplopia in 
1028 
adults with divergence insufficiency. Graefes Archive for Clinical and Experimental 
1029 
Ophthalmology 2013;251:1641-1644. 
1030 
19. Chaudhuri Z, Demer JL. Medial rectus recession is as effective as lateral rectus resection in 
1031 
divergence paralysis esotropia. Archives of Ophthalmology 2012;130:1280-1284. 
1032 
20. Chaudhuri Z, Demer JL. Sagging eye syndrome: connective tissue involution as a cause of 
1033 
horizontal and vertical strabismus in older patients. JAMA Ophthalmology 2013;131:619-
1034 
625. 
1035 
21. Rainin EA, Carlson BM. Postoperative diplopia and ptosis. A clinical hypothesis based on 
1036 
the myotoxicity of local anesthetics. Archives of Ophthalmology 1985;103:1337-1339. 
1037 

 
SAS1 Protocol v2.0 4-11-16 
6-2 
22. Johnson DA. Persistent vertical binocular diplopia after cataract surgery. American Journal 
1038 
of Ophthalmology 2001;132:831-835. 
1039 
23. Burgess D, Roper-Hall G, Burde RM. Binocular diplopia associated with subretinal 
1040 
neovascular membranes. Archives of Ophthalmology 1980;98:311-317. 
1041 
24. Brazis PW, Lee AG, Bolling JP. Binocular vertical diplopia due to subretinal neovascular 
1042 
membrane. Strabismus 1998;6:127-131. 
1043 
25. De Pool ME, Campbell JP, Broome SO, Guyton DL. The dragged-fovea diplopia syndrome: 
1044 
clinical characteristics, diagnosis, and treatment. Ophthalmology 2005;112:1455-1462. 
1045 
26. Wright KW. Mini-tenotomy procedure to correct diplopia associated with small-angle 
1046 
strabismus. Transactions of the American Ophthalmological Society 2009;107:97-102. 
1047 
 
1048