Grand Rounds 29 Feb 2016 Overminus spectacles as a treatment for IXT Jonathan M. Holmes

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Accreditation Mayo Clinic College of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.   Mayo Clinic College of Medicine designates this live activity for a maximum of  0.75 AMA PRA Category 1 Credits™.  Physicians should claim only the credit commensurate with the extent of their participation in the activity. CME Objectives 1) Identify/summarize/describe concepts related to clinical eye care 2) Apply new knowledge to relevant clinical situations. As a provider accredited by ACCME, Mayo Clinic College of Medicine, (Mayo School of CPD) must ensure balance, independence, objectivity and scientific rigor in its educational activities.   Course Director(s), Planning Committee Members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity.  Safeguards against commercial bias have been put in place.  Faculty also will disclose any off label and/or investigational use of pharmaceuticals or instruments discussed in their presentation.  Disclosure of this information will be published in course materials so those participants in the activity may formulate their own judgments regarding the presentation. Listed below are individuals with control of the content of this program who have disclosed… Relevant financial relationship(s) with industry: Raymond Iezzi, M.D. is a consultant to Alcon, Alimera, Vergent No relevant financial relationship(s) with industry: Dept. of Ophthalmology Planning Committee includes members of the Education Committee:   Drs. Sophie Bakri, Sanjay Patel, Keith Baratz, Andrew J. Barkmeier, Elizabeth Bradley, William Brown, John Chen, Amir Khan, Sunil Khanna, Leo Maguire, Michael Mahr, Brian Mohney, Wendy Smith, Linda Mrozek, Kari Sczepanski.

DISCLOSURE Jonathan M. Holmes Relevant Financial Relationship(s) None (only grant funding from NIH) Off Label Usage None

Presentation Learning Objectives To understand the current evidence-base for the use of overminus spectacles as a treatment for intermittent exotropia To identify factors that might predispose to successful treatment of intermittent exotropia with overminus spectacles

Question 1 Control of intermittent exotropia should be assessed with: Standardized timing of the tropic phase Prism and alternate cover test Near stereoacuity Standardized assessment on the synoptophore

Question 2 The current evidence suggests Overminus may be more effective when control is moderate Overminus may be more effective when control is poor There is no relationship between the effectiveness of overminus and level of control Overminus is ineffective as a treatment for intermittent exotropia

Index Case 5 year-old boy Hx - “left eye wanders particularly when tired or at end of day” VA 20/20 20/20 Full ductions D 25 X(T) comitant N 25 X(T) SLE Fundus Normal Cret +0.50 R +0.50 L

Diagnosis – Intermittent Exotropia One of the most common strabismus disorders of childhood Other Accommodative ET (28%) Sensory XT (3%) XT assoc with CNS (4%) Acquired Non-accomm ET (10%) CI XT (5%) Up to 1% of children under 11y in Olmsted CO MN ET assoc with CNS (7%) Intermittent Exotropia (17%) Sensory ET (4%) Paralytic ET (4%) Congen ET (5%)

IXT treatment options Observe Alternate patching e.g. 3hrs/day (? Anti-suppression therapy) Convergence exercises Surgery

Another non-surgical treatment option Overminus spectacles e.g. adding -2.50 sphere to each spectacle lens E.g. Cret -1.00 sph R -1.00 sph L Overminus Rx -3.50 sph R -3.50 sph L E.g. Cret +1.00 sph R +1.00 sph L Overminus Rx -1.50 sph R -1.50 sph L

Theoretical underpinnings Overminus stimulates accommodation which then stimulates convergence (therefore high AC/A ratio may be beneficial) Fusional vergence stimulates accommodation (we have a CA/A ratio) accommodation blurs distance VA requiring overminus for clarity

Previous studies of “Overminus” Small case series Differing amounts of overminus (-0.50 to -5.00) Differing methods of prescription (fixed versus titrated to control of IXT) No control groups No standardized outcome assessment No masking of outcome assessment

Intermittent Exotropia Study 3 (IXT3) A Pilot Randomized Clinical Trial of Overminus Spectacle Therapy for Intermittent Exotropia

To assess initial short-term response to overminus treatment Study Objectives To assess initial short-term response to overminus treatment

What is the question ? Is overminus treatment more effective than non-overminus treatment in the management of childhood intermittent exotropia?

Candidate 1o Outcome measures Angle of deviation? No – 2 cases can have same angle but very different Stereoacuity? No – stereoacuity often preserved Control? Yes - that is what others see

“Control” ? Proportion of the time the eyes are manifestly exotropic Ease of recovery when dissociated

“Control” ? Proportion of the time the eyes are manifestly exotropic Ease of recovery when dissociated

Mohney/Holmes office control score Description 5 Constant exotropia during a 30-second observation period (before dissociation) 4 Exotropia >50% of the time during a 30-second observation period (before dissociation) 3 Exotropia <50% of the time during a 30-second observation period (before dissociation) 2 No exotropia unless dissociated (10 seconds): recovery in > 5 seconds (worst of 3) 1 No exotropia unless dissociated (10 seconds): recovery in 1-5 seconds (worst of 3) Pure phoria: < 1 second recovery after 10-second dissociation (worst of 3) Phoric Tropic Control score described in a paper in Strabismus 2006. Control rated on 0 to 5 scale…… Scored separately for distance and near Mohney BG, Holmes JM. An office-based scale for assessing control in intermittent exotropia. Strabismus 2006;14:147-50.

30 second observation Constant exotropia – Grade 5 Exotropia > 50% of 30 seconds before dissociation – Grade 4 Exotropia < 50% of 30 seconds before dissociation – Grade 3 Score distance and near fixation separately

Three 10-second periods of dissociation first R, then L, then the eye that deviated longest – estimate how many seconds it takes to recover Grade by the worst of 3 trials (R, L, then worst) >5 seconds – grade 2 1-5 seconds - grade 1 <1 second – grade 0 (pure phoria)

But……control can be variable Distance control over the course of day 1 2 3 4 5 8:00 -10:30 10:31-13:00 13:01-15:30 15:31-18:00 Tropic Phoric 46% showed variable control ( >1 level) during a single day Control score There were 3 patients who changed at distance fixation…… All changed between phoria and tropia Worse level of control was not always later in day Patient 1 Patient 10 Patient 13 Assessment time

Multiple assessments of control Early am Late am Early pm Late pm Single Double Triple Mean of one or two or three measures (single, double, triple) Compared to 1. Day mean (of 12 measures) 2. Subsequent day mean (of 12 measures) Triple measures (mean of 3) were most representative of the patient

Current recommendations for assessing control – 3 assessments 30 sec observation 5 - constant Visit 4 ->50% 3 - <50% Mean of three assessments For Distance For Near 3 10-sec covers 2 - >5 secs 1 - 1-5 secs 0 - phoria

Back to the Pilot RCT

Refining the question in terms of the chosen primary outcome measure

Study Objectives To assess initial short-term response to overminus treatment Compare: Study group mean of distance IXT control scores (primary outcome)* Proportion of patients with improvement >=1 point in distance IXT control score* Adverse symptoms, near VA, & compliance *The distance IXT control score is the mean of 3 control tests at the visit.

Major Eligibility Criteria Age: 3 to <7 years IXT Distance control score ≥ 2 (mean of 3) Near control score ≠ 5 (mean of 3) ≥ 15∆ exo at distance by PACT Near deviation does not exceed distance deviation by >10 ∆ on PACT

Major Eligibility Criteria (cont.) No previous strabismus surgery No previous substantial overminus (>=1.00D) No non-surgical treatment for IXT within past 6 months (other than refractive correction) SE in both eyes between +1.00 and -6.00 inclusive No ADHD drugs or other drugs known to affect accommodation Wearing appropriate correction for ≥1wk if refractive error meets certain criteria

Study Flow Chart Enrollment Randomization Overminus GROUP Spectacles with full CR plus 2.50D overminus Observation GROUP (non-overminus spectacles or no spectacles) 2-WEEK PHONE CALL (FROM SITE) 8-WEEK Primary outcome exam (masked exam)

Study Treatment & Sample Size 58 patients enrolled at 21 sites We planned 50 patients, knowing that we would have 88% power to detect a 0.75 pt difference with a SD of 0.926 (1-sided test with alpha of 0.05) 58 patients enrolled and randomized (1:1) to: Observation (N=31) Non-overminus spectacles or no spectacles (if correction not needed) Overminus (N=27) Spectacles with 2.50D overminus

Post-randomization Spectacle Wear in Observation Group

Baseline: XT Control at Distance N/A N/A Distance Exotropia Control Score (mean of 3 testings)

Baseline: XT Control at Near Near Exotropia Control Score (mean of 3 testings)

Baseline: PACT at Distance N/A Magnitude of Exodeviation by PACT at Distance (∆) Note: PACT at distance had to be at least 15 PD for eligibility.

Magnitude of Exodeviation by PACT at Near (∆) Baseline: PACT at Near Magnitude of Exodeviation by PACT at Near (∆)

Baseline Stereoacuity at Near Baseline Near Stereoacuity (arcsec)

Visit Completion

Visit Completion Observation (N=31) Overminus (N=27) 2-week call Completed Missed 30 (97%) 1 (3%) 27 (100%) 0 (0%) 8-week outcome visit 31(100%)

Weeks of Overminus Spectacle Wear Possible Treatment Compliance Weeks of Overminus Spectacle Wear Possible

Weeks Overminus Patients Had Overminus Spectacles Mean = 7 weeks Range = 4 -11 weeks Weeks Between Spectacle Receipt and 8-Week Visit

Compliance with Overminus* *Based on parental report and discussion with investigator.

Primary Outcome

8-week Mean Distance Control Difference = -0.75 (-1.42 to -0.07) P = 0.03 for one-sided test Observation (N=31) Overminus (N=27)

8-week: Mean Distance Control Difference = -0.75 (-1.42 to -0.07) P = 0.03 for one-sided test 8-wk Distance Control Score (mean of 3 testings)

8-week Change in Distance Control Percentage of Patients Worse Mean change = -0.4 Mean change = -1.2 N/A N/A N/A N/A Better Percentage of Patients

8-week Distance Control Treatment Response (≥ 1 point improvement) Difference = 20% (-6% to 45%) P = 0.07 for one-sided test

Improvement in control by level of baseline control Does improvement depend on baseline control?

8-week Mean Change in Distance Control According to Baseline Control Observation Overminus N Mean Change (points) 2 to <3 13 0.1 pt 12 -0.5 3 to < 4 7 6 -0.7 4 to <5 11 -1.0 9 -2.5

>=1 point improvement in distance control 8-week Distance Control Treatment Response According to Baseline Control Baseline Distance Control Observation Overminus N >=1 point improvement in distance control 2 to <3 13 3 (23%) 12 6 (50%) 3 to < 4 7 4 (57%) 6 3 (50%) 4 to <5 11 4 (45%) 9 7 (78%)

Variability and regression to the mean Start study here Patient only enrolled if worse than threshold for inclusion Worse Parameter X Threshold Better Visit 1 Visit 4 Visit 2 Visit 3 If you only enroll with “X worse than…” then you will see “apparent improvement” – due to variability and regression to mean

But in an RCT … Regression to the mean will be equal between groups

So this effect of baseline control is likely to be real Distance Control Observation Overminus N Mean Change (points) 2 to <3 13 0.1 pt 12 -0.5 3 to < 4 7 6 -0.7 4 to <5 11 -1.0 9 -2.5

Safety Data

Safety Observation N=31 Overminus N=27 Esodeviation* 0 (0%) 1 (4%) Reduction of ≥ 2 lines distance VA** 2 (8%) Reduction of ≥ 2 lines binocular near VA*** *Overminus: 3PD esodeviation **Observation: 20/16 to 20/25 OS Overminus: 20/20 to 20/32 OS, 20/ 20 to 20/40 OS ***Observation: 20/20 to 20/32

Symptom Survey Data

Has your child had headaches? 8-week Parental Report of Symptoms

Has your child had eyestrain? 8-week Parental Report of Symptoms

Has your child avoided reading or doing things up close? 8-week Parental Report of Symptoms

Has your child reported blurry vision? 8-week Parental Report of Symptoms

Has your child looked over his/her spectacles? 8-week Parental Report of Symptoms

Has your child taken spectacles off when should be wearing them? 8-week Parental Report of Symptoms

Has your child complained that spectacles hurt ears and/or nose? 8-week Parental Report of Symptoms

Limitations Pilot study, small sample size Generalizable only to children 3 to 7 yrs with similar characteristics Includes hyperopia only up to +1.00 D We don’t know if works over wider range of refractive error Likely overestimated % with response 1-line of control improvement within test-retest. Expected ~20% to ‘respond’ by chance alone.

Conclusions Overminus spectacles improve distance control (after 8 weeks) Overminus spectacles appear to improve distance control particularly well in patients with very poor control (with a control score of 4 to 5)

How pilot study results pertain to possible full-scale, long-term RCT

IXT5 – possible full-scale longer term overminus study

Timing of outcome visits? Children XX years old with IXT (with control score of 2 or worse) Overminus Observation ? Should there be escape clauses If so, what should they be? Long-term f/u ON treatment ? 12 mo Final f/u OFF treatment ? 18 mo

Question 1 Control of intermittent exotropia should be assessed with: Standardized timing of the tropic phase Prism and alternate cover test Near stereoacuity Standardized assessment on the synoptophore

Question 1 Control of intermittent exotropia should be assessed with: Standardized timing of the tropic phase Prism and alternate cover test Near stereoacuity Standardized assessment on the synoptophore

Question 2 The current evidence suggests Overminus may be more effective when control is moderate Overminus may be more effective when control is poor There is no relationship between the effectiveness of overminus and level of control Overminus is ineffective as a treatment for intermittent exotropia

Question 2 The current evidence suggests Overminus may be more effective when control is moderate Overminus may be more effective when control is poor There is no relationship between the effectiveness of overminus and level of control Overminus is ineffective as a treatment for intermittent exotropia

Thank you