current clinical case reorts & research you should incorporate into your mode of practice now!

Dominick Maino, OD, MEd, FAAO, FCOVD-A Moderator

Featuring the Best of AOA's 2016 Poster PresentationsSaturday, July 2nd 8-10AM

Current Clinical Case Reports and Research You Should Incorporate into your Mode of Practice Now!

The Sunshine Act First Year Results: The Status of Optometry Primary Author: Erik Mothersbaugh, OD

Residual peroxide levels after neutralization of two marketed one-step hydrogen peroxide systems

Primary Author: Jessie Lemp, MS, DrPH

The Cat's Out of the Bag: Serial Analysis of Neuroretinitis Through Spectral Domain OCT and Humphry Visual Field Assessment

Primary Author: Amy A. Puerto, OD

Safety and Efficacy of Latanoprostene Bunod for Lowering of Intraocular Pressure in Open-Angle Glaucoma or Ocular Hypertension

Primary Author: Murray Fingeret, OD

Validation Study of Visual Objectives Biomarkers for Acute Mild Traumatic Brain InjuryPrimary Author: José E. Capó-Aponte, OD, PhD

2016 AOA’s Best Presentations

Cochrane Reviews

http://www.cochrane.org/

… a global independent network of researchers, professionals, patients and people interested in health…

Levels of Research

http://www.cochrane.org/

Clinician’s View of Researchers

Researcher’s view of Clinicians

Poster SessionMy Thanks to the AOA 2016 Abstract Review Committee

William McAllister, Elizabeth Wyles, Sunny Sanders, Sarah Hinkley, Christine Allison, Jennifer Harthan, Aurora

Denial

176 posters submitted 50% of Posters accepted

Criteria for acceptance similar to those used by other well respected organizations (clinical aspects emphasized)

Reasons for non-acceptance: Did not follow instructionsData does not support conclusionsNot unique

Poster Session

Preview session on Friday, July 1, 2016 (10:00am-6:00pm)

Interactive session on Saturday, July 2, 2016

(11:00am-2:00pm)

Poster Session 2017Please submit Case reports, Case series, Clinical research, etc. in all areas of optometry for 2017 when the call for abstracts goes out!

Informational Posters Accepted (These also need to be well done and cannot be a sales pitch for a particular product or service. This is NOT a review of the literature.)

This Morning’s PresentationThe committee judged these posters to be notable and worthy to be highlighted in this fashion

Questions welcome at the end of each of today’s presentations

The Sunshine Act First Year Results: The Status of

Optometry

Erik Mothersbaugh, ODElizabeth Wyles, ODJordan Keith, OD

Brennan TA, et al. Health industry practices that create conflicts of interest. JAMA. 2006; 295: 429-433

69%of Americans say that drug makers hold too much sway over physicians prescribing habits

2010 Consumer Reports National Research Center poll

Affordable Care Act: Section 6002SUMMARY: This final rule will require applicable manufacturers of drugs, devices, biologicals, or medical supplies covered by Medicare, Medicaid or the Children’s Health Insurance Program (CHIP) to report annually to the Secretary certain payments or transfers of value provided to physicians or teaching hospitals (‘‘covered recipients’’). In addition, applicable manufacturers and applicable group purchasing organizations (GPOs) are required to report annually certain physician ownership or investment interests. The Secretary is required to publish applicable manufacturers’ and applicable GPOs’ submitted payment and ownership information on a public Web site.

CMS Open Payments Database• August 1, 2013: Industry required to start data capture

• December 31, 2013: End of first reporting period

• January 1, 2014: Beginning of second reporting period

• December 31, 2014: End of second reporting period

Chang, JS. The physician payments sunshine act. Ophthalmology 2015; 122(4): 656-661.

Design• Retrospective data review

• Participants: Optometrists registered in CMS Open Payments database

• Data collected: All general payments made to optometric physicians between January 1, 2014 and December 31, 2014

What is considered a “general payment”?• Cash or Cash Equivalent

• Consulting fees• Speaking fees• Honoraria• Royalties

• In-Kind Items and Services• Food and Beverage• Travel and Lodging• Education

What is NOT considered a “general payment”?

• Ownership/Investment payments

• Research-related payments

Results: National• Transactions: 165,035• Optometric Physicians Accepting Payments: 36,426

• Total Payments: $18,289,817• Average Transaction Value: $111

• Average Payment per Physician: $502

Results: National• Range: $1 - $406,392

• Payments made to Top 10% of Payment Recipients: $13,166,996

72% of the total $18.3 M went to physicians in the highest 10%

Results: State-by-State ComparisonStates that Rank in Top 10 for both Total Payments and Average Payment per Provider

State Total Payment Rank Average Payment Rank

California 1st 8th

Florida 4th 9th

North Carolina 5th 3rd

Pennsylvania 3rd 5th

Utah 8th 1st

Results: State-by-State ComparisonStates that Rank in Bottom 10 for both Total Payments and Average Payment per Provider

State Total Payment Rank Average Payment Rank

Alaska 45th 43rd

Delaware 48th 47th

Maine 47th 50th

Montana 49th 49th

New Mexico 44th 45th

North Dakota 43rd 41st

South Dakota 46th 48th

Do financial relationships with industry influence physicians’ behavior?

“The present extent of physician-industry interactions appears to affect prescribing and professional behavior and should be addressed at the level

of policy and education.”

Wazana A. JAMA 2000 Jan 19;283(3):373-80

“A minority of doctors (40%) thought that industry involvement created a conflict of interest but the majority of doctors (86%) thought that it did not

create a bias in their own drug selection.”

Rutledge et. Al. Pharmacoepidemiology and Drug safety. 2003; 12: 663-667.

Conclusions

• Financial relationships with industry are widespread in the profession of Optometry, with over 36,000 ODs participating.

• The majority of total dollars paid to Optometrists (72%) goes to a relative minority of providers (10%).

“Guidelines establishing thresholds, such as the arbitrary amount of $100, are based on the belief that there is a

direct “dose response”—that the risk of bias increases as the value of the gifted

item increases. There is no level, however, below which it is guaranteed that marketing wares have no effect on

the recipient.”

Katz, D. et al. All gifts large and small: Toward an understanding of the ethics of pharmaceutical industry gift-giving. The American Journal of Bioethics; 3(3): 39-46.

Relationships with Industry

Optometrists should avoid situations and activities that would not be in the best interest of their patients.

Any financial and/or material incentive offered by industry that creates an inappropriate influence on an optometrist’s clinical judgment should be avoided

AOA Standards of Professional ConductSection E, Part 1-E – Non Patient Professional Relationships

Conflict of Interest

The care of a patient should never be influenced by the self-interests of the provider.

Optometrists should avoid and/or remove themselves from any situation that presents the potential for a conflict of interest where the optometrist’s self interests are in conflict with the best interest of the patient

Disclosure of all existing or potential conflicts of interest is the responsibility of the optometrist and should be appropriately communicated to the patient

AOA Standards of Professional ConductSection B, Part 4-B – Nonmaleficence (“do no harm”)

References• "Health Policy Brief: The Physician Payments Sunshine Act," Health Affairs, October 2, 2014.

• Lichter, PR. Debunking myths in physician-industry conflicts of interest. Ophthalmology 2008; 146(2): 159-171.

• Wazana A. Physicians and the pharmaceutical industry: Is a gift ever just a gift? JAMA 2000; 283: 373-380.

• Katz, D. et al. All gifts large and small: Toward an understanding of the ethics of pharmaceutical industry gift-giving. The American Journal of Bioethics; 3(3): 39-46.

• Epstein, AJ. et al. Does exposure to conflict of interest policies in psychiatry residency affect antidepressant prescribing? Medical Care; 51(2): 199-203.

• Austad, KE. et al. Association of marketing interactions with medical trainees’ knowledge about evidence-based prescribing: Results from a national survey. JAMA Intern Med 2014; 174(8): 1283-1289.

• Segovis, CM. et al. If you feed them, they will come: A prospective study of the effects of complimentary food on attendance and physician attitudes at medical grand rounds at an academic medical center. BMC Medical Education 2007; 7(22).

• Lichter, PR. Implications of the sunshine act – Revelations, loopholes, and impact. Ophthalmology 2015; 122(4): 653-655.

• Agrawal, SA. et al. The sunshine act – Effects on physicians. N Engl J Med 2013; 368(22): 2054-2057.

• Chang, JS. The physician payments sunshine act. Ophthalmology 2015; 122(4): 656-661.

• Brennan, TA. et al. Health industry practices that create conflicts of interest: A policy proposal for academic medical centers. JAMA 2006; 295(4): 429-433.

• Rutledge P, et al. Do doctors rely on pharmaceutical industry funding to attend conferences and do they perceive that this creates a bias in their drug selection? Results from a questionnaire survey. Pharmacoepidemiol Drug Safety 2003; 12: 663-667.

• Epstein AJ, et al. Does exposure to conflict of interest policies in psychiatry residency effect antidepressant prescribing? Med Care. 2003 February; 52(2): 199-203

• King M et al. Medical school gift restriction policies and physician prescribing of newly marketed psychotropic medications: difference-in-differences analysis.

Questions ?

Questions?

1.) How do the professions of optometry and ophthalmology compare with respect to these payments?2.) Why do you think so much of the money goes to a relative few physicians?3.) Have any optometry schools instituted policies restricting industry interaction?

A Comparison of Residual Peroxide Profiles after Neutralization of Two Marketed One-Step

Hydrogen Peroxide Systems Jessie Lemp, MS, DrPH; Jami R. Kern, PhD; Amanda Shows, BS; and Huagang Chen, MS

Alcon Laboratories, Inc.Fort Worth, TX, USA

Jessie Lemp, Jami R. Kern, Amanda Shows, and Huagang Chen are employees of Alcon Laboratories, Inc.

44

Background• Common one-step hydrogen peroxide lens disinfecting systems work by use of a 3% H2O2 buffered solution, which is neutralized by a platinum catalyst disc during lens storage.

• Clear Care® (Alcon) brand 3% H2O2 systems recommend a 6-hour recommended storage time out to 100 cycles.

• PeroxiClear® (Bausch & Lomb) 3% H2O2, containing a platinum-modulating compound, recommends a 4-hour storage time and a max of 35 cycles.

• Both the Clear Care® brands and PeroxiClear® have demonstrated similar, high levels of disinfection efficacy.3,4

• Residual H2O2 can remain after the disinfection cycle; if these levels are too high, ocular discomfort can result.1,2

45

1. Paugh JR et al. Am J Optom Physiol Opt. 1988;65:91-98. 2. McNally J. CLAO J. 1990; Jan-Mar; 16 (suppl 1): S46-51. 3. Gabriel et al. Poster presented at BCLA Meeting, Liverpool, UK May 29-31, 2015. 4. Cordero D et al. Poster presented at AAOpt Meeting, Seattle, WA Oct 22-27, 2013.

Purpose•To compare the residual H2O2 profiles of Clear Care Plus with HydraGlyde (CCP) and PeroxiClear (PC) after neutralization in laboratory-cycled cases and patient-used cases.

46

Methods: (in vitro analysis)• Neutralization rates of CCP and PC were evaluated.

• All cases (n=3/time point) were first cycled one time overnight. • On the second cycle:

47

30

45

60

120

240

360

5

15

Minutes

An aliquot of product solution recovered for the assay of

remaining H2O2 in parts per million (ppm) using UV spectroscopy.

H202 levels determined by titration with potassium permanganate

Method: (in vitro analysis)• Residual H2O2 in the two systems was compared at room temperature through 100 neutralization cycles

without lenses.• Each cup was filled with 10 mL of corresponding test solution (n=5/system), capped tightly, and allowed to

neutralize for the recommended storage time.

• At each test cycle, an aliquot of product solution recovered for the assay of remaining H2O2 (ppm) using UV spectroscopy.

48

1..............15..............30..............45..............60..............75..............90.........100

@ 4hrs @ 6hrs

CyclesEach non-test cycle lasted ≥4hrs or ≥6hrs respectively

Methods (ex vivo analysis)

Day 30 Used Cup

Day 30 Used Cup

Day 1-30

CCPDay 30

Used CupDay 30

Used Cup

Day 1-30

PCDay 1-30

PC

@ 4hrs @ 6hrs

An aliquot of product solution recovered for the assay of remaining H2O2 in parts per million (ppm) using UV spectroscopy.

Neutralization rates by way of testing residual H2O2 at 2, 3, and 4 hours of neutralization (CCP and PC) and at 6 hours (CCP) were also determined using 10 randomly selected used cases per product.

10 mL of the appropriate solution (CCP or PC) was added to each used case

50

Results (in vitro analysis)

• CCP had significantly lower residual H2O2 than PC at all tested neutralization time points up to 120 minutes in unused cases (P < .05), with a trend towards lower residual H2O2 at 240 and 360 minutes (P < .10).

Neutralization Rates for CCP and PC over 6hrs (n = 3)

Results (in vitro analysis)

51

• Residual H2O2 concentrations of CCP were significantly lower than those of PC after neutralization cycles of 1, 30, 60, and 90, corresponding to initial and 1, 2, and 3 months, respectively (P<.05).

Neutralization Profiles of CCP and PC at Manufacturer-Recommended Storage Time (n = 5)

Note: The Limit of Quantitation (LOQ) is 5 ppm. Data below 5 ppm are <LOQ. Values are mean ± SD.

*P< .05

Results (ex vivo analysis)

52

Mean Residual H2O2 for 30-Day Used CCP and PC Systems at Manufacturer-Recommended Storage Times (n=130)

• In 30-day used cases, mean SD residual H2O2 for CCP and PC at neutralization time was 26.2 ± 41.17 and 229.7 ± 280.13, respectively (P<.001).

Results (ex vivo analysis)

53

Neutralization Rate Profiles for 30-Day Used CCP and PC Systems (n = 10)

• CCP had lower residual H2O2 than PC at 2, 3, and 4 hrs. (P<.05 at 2, 3 hrs.).• Residual H2O2 was <100 ppm in the 30-day used CCP system by 3 hours of neutralization.

†Not tested at 5 hr. ‡PC not tested at 6 hr.

Results (safety analysis)

54

Ocular Adverse Events (Adverse Device Effects)

• There was a higher incidence of related adverse device effects (ADEs) in subjects using PC (11 ADEs in 5 subjects) than in those using CCP (2 ADEs in 1 subject).

Conclusions• In both laboratory-cycled and patient-used cases, the manufacturer-recommended 6-hour neutralization time of CCP allows for more complete neutralization of H2O2 than the 4-hour neutralization time recommended with PC.

• Both the CCP and PC systems used by study subjects resulted in higher residual H2O2 concentrations at neutralization time compared to the systems cycled in the laboratory; however, the relative increase was larger for PC.

55

Discussion• Of the 30-day used lens cases collected, 98.5% of CCP and 20.0% of PC systems at recommended storage time showed mean residual peroxide ≤ 100 ppm, the ocular detection threshold.1

• Further research should be conducted to understand the clinical implications of these findings.

• Given peroxide solutions are often recommended to sensitive contact lens wearers, ECPs should consider these findings when recommending a solution and educating their patients on proper use.

561. Paugh JR, et al. Am J Optom Physiol Opt. 1988;65:91-98.

Questions ?

57

The Cat's Out of the Bag! Serial Analysis of Neuroretinitis Through Spectral Domain OCT, Fundus Photography, and Humphrey

Visual Field Assessment

Amy Puerto, O.D.Family Practice ResidentBond-Wroten Eye Clinic

Hammond, Louisiana (New)

Financial Disclosure

I have no financial interest in any commercial or pharmaceutical entity mentioned during this presentation.

Case Presentation• Case Hx: Initial Visit

• New patient: 30-year-old Arab Male • Presenting Complaint: Painless visual loss in his right

eye x 3 days, described as seeing a “blurry-gray spot” near the center-right of his vision that had gotten bigger.

• Ocular Hx: • Wears spectacles/contact lenses denies history of eye

disease or eye surgeries• Systemic Hx:

• Patient presented with concurrent history of fever, fatigue, headaches, and chills x 1 week.

• Patient denied pain, parasthesia, numbness, motor weakness or gait changes.

• Patient was not on any medications and denied smoking and alcohol use.

• NKDA• (+) Tylenol PRN

• Family Hx: • Mother: (+) Diabetes, HTN• Father: (+) Cardiovascular disease

• Examination:• VA’s with CLs : 20/400 EF* OD, 20/20 OS• Pupils: trace APD OD• EOMs & Cover Test Unremarkable• CVF Full OD, OS but patient reported unable

to “see” doctor’s left side of face when performing test

• Color Vision: Ishihara 14/14 OD, OS**• Red Cap Test: (+/?)**

• No lymphadenopathy • BP: 113/76 Pulse: 60

• SLE: • Anterior Segment: Unremarkable OD, OS • Dilated Fundus Examination…

*EF- Eccentric Fixation

Fundus PresentationLeft EyeRight Eye

OCT Analysis-Retina Left Eye Right Eye

OCT Analysis- Optic Nerve

Visual Field Analysis Left Eye Right Eye

Review of Differential Diagnoses1. Optic Neuritis assoc. MS

2. Ischemic Optic Neuropathy NAION

AAION assoc. GCA

3. Papilledema

4. Retinal Vein Occlusion

5. Neuroretinitis

Assessment/Plan Assessment:

• Neuroretinitis suspect Cat Scratch Disease etiology per HxPlan:

• Lab Work-up • CBC w/ Diff, ESR, C-reactive Protein, and Bartonella Henselea Titer

• Rx’d doxycycline monohydrate 100mg p.o. BID x 30 days prophylactically• Patient advised to RTC x 1 week for f/u with VF and OCT until resolution.

Time to be the CLINICIAN!• Be systematic in your differentials and remember: “Common things happen commonly.”

• Cost-effective laboratory testing and clinical observation can be used to properly diagnose cases of optic nerve edema.

Assessment and Plan Cont’dLab Results Results Reference Range

WBC 21.4 3.4-10.8

Neutrophils 12.4 1.4-7.0

Lymphs 4.5 0.7-3.1

Monocytes 3 0.3-0.9

RBC 4.65 4.14-5.80

Platelets 265 150-379

ESR*6,7 18 mm/h 0-20mm/h

CRP 13m/L 0-7mg/L

Bartonella henselae Antibody IgG 1:1280 <1:320

Bartonella henselae Antibody IgM 1:200 <1:100

One Week Follow-up

• At one week f/u patient had confirmed labs showing elevated WBC Count and a Positive Bartonella titer.

• Patient VA’s remained at 20/400. • Confirmed Diagnosis of Neuroretinitis associated with Cat Scratch Disease.

• Cont. Doxy BID until medication is gone.

Cat Scratch Disease (CSD)• Cat scratch disease (CSD) is a systemic infection caused by the bacteria Bartonella henselae, with approximately 22,000 cases U.S./year. 1

• Patients contract the infection after being scratched, bitten, or licked by a cat and commonly report a virus-like illness.

• Demographic: Persons of all ages and ethnicities, but is more often seen in pediatric populations or those between the ages 30 and 40

• Ocular involvement occurs in ~10% of CSD cases1,2,5: • Parinaud's oculoglandular syndrome: granulomatous conjunctivitis with associated lymphadenopathy• Focal chorioretinitis• Neuroretinitis

• Positive Bartonella Henselae titer

• The condition tends to be self-limiting, for a period of eight to 12 weeks, though oral doxycycline 100mg BID for two to four weeks is widely published as the primary treatment choice to shorter the duration of symptoms. 3,4,5

Neuroretinitis • Only 1% to 2% of patients with Cat Scratch Disease develop neuroretinitis!1,2

• Patient Symptoms5: • Preceding or concurrent flu-like illness* • Decreased/blurry vision in one eye • Decreased visual field in one eye…”spot missing in vision”• red eye (in patients with POGS)

• Clinical Features:• Disc swelling in the presence of an exudative macular star formation.1,3

• In cases of extreme disc edema, a neurosensory detachment may occur• Disc edema usually precedes macular star formation by 2-4 weeks. 2,4

• APD may be present• Lymphadenopathy (maybe subclinical) • Enlarged blind spot on visual field testing

• While neuroretinitis associated with cat scratch disease is well documented in the literature, no studies have visualized the sequential progression of retinal structures on OCT nor mapped a patient’s visual field from disease onset to resolution. **

Review of Treatments• Observation • Antibiotic Approach

• Doxycycline• Dosages• Contraindications• Side Effects• Alternatives1,2

• Other therapies to be considered…• For the ONH inflammation? • For the Macular Edema?• Should topical, oral, injections be considered?8,9

COLOR VISION10,11

Week 1 & 2 PresentationOCT Visual Field

One Week Later

Two Weeks Later

VA’s: 20/200

VA’s: 20/400

The Progression Continues… Weeks 3-5 Weeks 6-8

Week 3 VA’s: 20/100

Week 4 VA’s: 20/80

Week 5 VA’s: 20/60+

Week 6 VA’s: 20/40-

Week 7 VA’s: 20/25

Week 8 VA’s: 20/20-2

Week 1 VA’s: 20/400

Week 8 VA’s: 20/20-2

ONH Progression

Visual Field Progression Analysis

What About That Fundus View?

Conclusion • Neuroretinitis is an inflammatory optic neuropathy characterized by optic disc edema and exudates within the fovea in a macular star pattern.

• Cat scratch disease is the single most common cause of neuroretinitis.• Bartonella Henselae Titer confirmative • False negatives may be present in early disease progression

• OCT and VF analysis are valuable tools that can be used to monitor disease resolution in cases of Neuroretinitis from Cat Scratch Disease.

• Neuroretinitis generally has a good prognosis with spontaneous improvement, but oral antibiotics appear to hasten recover time.

• Changes in the foveal RPE tend to be permanent and residual “blind spots” in the vision may persist.

• Having one episode of cat scratch disease usually makes patients immune for the rest of their lives.1,5

Sources1. Longmuir RA, Lee A. Cat-Scratch neuroretinitis (Ocular bartonellosis): 44-year-old female with non-specific "blurriness" of vision, left

eye (OS). EyeRounds.org. March 31, 2005. March 2016

2. Chappel, Michael. "Spotting Bartonella-Associated Uveitis." Review of Ophthalmology. Web. 21 Mar. 2011. March 2016.

3. Habot-Wilner, Z., D. Zur, M. Goldstein, D. Goldenberg, S. Shulman, A. Kesler, M. Giladi, and M. Neudorfer. "Macular Findings on Optical Coherence Tomography in Cat-scratch Disease Neuroretinitis." Eye. Nature Publishing Group. Web. 25 Aug. 2011.February 2016.

4. Rob Foroozan. "What Is Neuroretinitis?" Healio: Medical News and Journals. Web. September 2014. Apr. 2016.

5. Ling, Jeanie. "Big Red flags in Neuro-ophthalmology: Optic Disc Edema and the Presence of Subretinal Fluid." Neuro-ophthalmology. Stanford. Can J Ophth: 48:1. Feb 2013. Web. Feb. 2016.

6. Harrison, Michael. "Erythrocyte Sedimentation Rate and C-reactive Protein." Aust Prescriber An Independent Review. Department of the Interior. 38:93-4. 1 June 2015. Web. May 2016.

7. Feldman, M., B. Aziz, and GN Kang. "C-reactive Protein and Erythrocyte Sedimentation Rate Discordance: Frequency and Causes in Adults." National Center for Biotechnology Information. U.S. National Library of Medicine. 161(1):37-43. 23 Aug. 2012. Web. May 2016.

8. Accorinti, Massimo. “Ocular Bartonellosis.” Int J Med Sci. 6(3):131-132; 19 March 2009. Web. May 2016

9. Purvin, Valerie, Nicholas Ranson, and Aki Kawasaki. "Idiopathic Recurrent Neuroretinitis." Arch Ophthalmol. JAMA Ophthalmology, 121(1):65-67; Jan. 2003. Web. May 2016.

10. Katz, Barrett. “The Dyschromatopsia of Optic Neuritis: A Descriptive Analysis of Data from the Optic Neuritis Treatment Trial.” Transactions of the American Ophthalmological Society 93 (1995): 685–708. Print. May 2016.

11. Schneck, Marilyn, and Gunilla Haegerstrom. "Color Vision Defect Type and Spatial Vision In the Optic Neuritis Treatment Trial." Investigative Ophthalmology & Visual Science 38.11 (1997): 2278-289. PubMed. Web. May 2016.

Questions ?

Integrated Safety and Efficacy of Latanoprostene Bunod for Lowering of

Intraocular Pressure in Open Angle Glaucoma or Ocular Hypertension

Murray Fingeret, ODChief of the Optometry Section

Dept. of Veterans Administration New York Harbor Health Care SystemClinical Professor

State University of New York College, College of Optometry

Jason Vittitow, PhDDirector, Clinical AffairsBausch + Lomb (New)

RELEVANT FINANCIAL DISCLOSURES• Murray Fingeret, ODBausch + Lomb Consultant• Jason Vittitow, PhDBausch + Lomb Employee

85

SPONSORBausch + Lomb, 400 Somerset Corporate Blvd, Bridgewater, NJ

DISCLOSURE OF APPROVED USE: This drug has not been approved by the U.S. Food and Drug Administration (FDA)

Nitric Oxide and Glaucoma

86

Patients with primary open-angle glaucoma (POAG) have lower levels of NO synthase activity in the trabecular meshwork (TM), Schlemm’s canal, and ciliary muscle and reduced NO metabolites in the aqueous humor.1,2

NO donors lower IOP in normal and POAG eyes.3-9 A major site of action for NO donors is the TM/Schlemm’s canal.6-11

1. Nathanson JA, et al. Invest Ophthalmol Vis Sci 1995;36:1774-1784. 2. Galassi F, et al. Br J Ophthalmol 2004;88:757-60. 3. Wizemann AJ, et al. Am J Ophthalmol 1980;90:106-109. 4. Kotikoski H, et al. J Ocul Pharmacol Ther 2002;18:11-23. 5. Behar-Cohen FF, et al. Invest Ophthalmol Vis Sci 1996;37:1711-5. 6. Nathanson JA, et al. J Pharmacol Exp Ther 1992;260:956-965 7. Heyne GW, et al. Invest Ophthalmol Vis Sci 2013;54:5103-5110. 8. Schuman JS, et al. Exp Eye Res 1994;58:99-105. 9. Lei Y, et al. Invest Ophthalmol Vis Sci 2015;56:4891-8. 10. Becquet F, et al. Surv Ophthalmol 1997;42:71-82. 11. Cavet ME, et al. Invest Ophthalmol Vis Sci 2014;55:5005-15.

Latanoprostene Bunod (LBN):An NO-donating Prostaglandin F2α Analog

Latanoprost acid

1,4-Butanediol

NO

Krauss AH, et al. Exp Eye Res 2011;93:250-5

HO

HO

HO

OH

O

HO

HO

HO

O

O

ON

O

O

HOO

NO

O

Butanediol mononitrate

Nitric oxide

HOOH

LBN: A dual-acting IOP lowering agent

FP receptor

Latanoprost acid

Matrix metalloproteinases

Extracellular matrix remodeling

Uveoscleral outflow

Reduced IOP

Nitric oxide

cGMP/PKG

Trabecular meshwork (TM) cell relaxation

TM/Schlemm’s canal outflow

Soluble guanylyl cyclase

Lindsey JD et al. Invest Ophthalmol Vis Sci. 1997;38:2214-23Schachtschabel U et al. Curr Opin Ophthalmol. 2000;11(2):112-5 Cavet ME et al. Invest Ophthalmol Vis Sci. 2014;55:5005-15

HO

HO

HO

O

O

ON

O

O

Pooled analysis of two Phase 3 studiesLBN 0.024% (QD) vs. timolol 0.5% (BID) in OAG/OHT

89

Primary objective Demonstrate non-inferiority of mean IOP reduction over 3 months of LBN 0.024% QD in the evening to timolol maleate 0.5% BID

Secondary objective Demonstrate the superiority of mean IOP reduction over 3 months of LBN 0.024% QD in the evening to timolol maleate 0.5% BID

Primary efficacy endpoint IOP measured at 8 AM, 12 PM, and 4 PM at Weeks 2 and 6 and at Month 3

Secondary efficacy endpoints Proportion of subjects with IOP ≤ 18 mm Hg consistently at all 9 time pointsProportion of subjects with IOP reduction ≥ 25% from baseline consistently at all 9 time points

Safety variables Incidence of ocular and systemic adverse eventsOcular signs, BCVA, vital signs, investigator assessed conjunctival hyperemia

Inclusion Criteria and Demographics

90

Table 1. Subject DemographicsLBN 0.024% (N=562) Timolol 0.5% (N=269)

Age (Mean, SD) 64.9 (10.0) 63.7 (10.5)

Gender (n,%)MaleFemale

234 (41.6)328 (58.4)

113 (42.0)156 (58.0)

Race (n,%)WhiteAfrican AmericanAsianOther

421 (74.9)133 (23.7)5 (0.9)3 (0.5)

197 (73.2)70 (26.0)2 (0.7)

0

Treatment-Naïvea (n,%)YesNo

165 (29.4)397 (70.6)

68 (25.3)201 (74.7)

aTreatment-naïve = subjects who were not under treatment with IOP-lowering medication at screening and had no documented IOP-lowering medication in their medical history 30 days prior to screening.

Mean/median IOP ≥ 26 mm Hg at a minimum of 1 time point, ≥ 24 mm Hg at a minimum of 1 time point, and ≥ 22 mm Hg at 1 time point in the same eye

Mean/median IOP ≤ 32 mm Hg in both eyes at all 3 measurement time points

Primary efficacy endpoint: Mean IOP in the study eye (ITT population)

91Bausch + Lomb, data on file.

LBN-treated subjects had significantly greater IOP reductions with a mean diurnal decrease from baseline of 32.0% at Month 3 vs. 27.6% for timolol-treated subjects

Week 6 Month 3Week 2

*

* **

* *

*

* *

*P<0.001 vs. timolol

8 AM 12 PM 4 PM 8 AM 12 PM 4 PM 8 AM 12 PM 4 PM15

16

17

18

19

20M

ean

IOP

(mm

Hg)

LBN 0.024% Timolol 0.5%

Baseline IOP, mean (SD):LBN = 26.7 (2.4) mm Hg Timolol = 26.5 (2.3) mm Hg

Secondary efficacy endpoint: Mean IOP reduction by visit and time (ITT population)

Week 2 Week 6 Month 38 AM 12 PM 4 PM 8 AM 12 PM 4 PM 8 AM 12 PM 4 PM

LBN Mean CFB (mm Hg) -8.7 -8.3 -7.6 -9.0 -8.6 -7.9 -9.0 -8.7 -8.0

Timolol Mean CFB (mm Hg)

-7.7 -7.2 -6.7 -7.8 -7.5 -6.7 -7.7 -7.3 -6.6

Treatment Difference -1.1 -1.1 -1.0 -1.2 -1.1 -1.2 -1.2 -1.3 -1.4Primary Objective NI NI NI NI NI NI NI NI NI

Secondary Objective P<0.001 for all time pointsNI: Claimed if upper CI < 1.5 mm Hg at all time points and < 1.0 mm Hg for at least 5 of 9 time points.Superiority: Claimed if upper CI < 0 mm Hg at all time points.CFB = change from baseline

Bausch + Lomb, data on file.

LBN lowered IOP by 7.6-9.0 mm Hg (pooled studies) and 7.5-9.1 mm Hg (individual studies). IOP lowering exceeded that of timolol by >1 mm Hg at each time point.

Secondary efficacy endpoint: Mean % IOP reduction at 3 months (ITT population)


LS mean reduction from baseline in mean IOPMean IOP results use LOCF; no imputation applied to mean diurnal IOP

8 AM 12 PM 4 PM Diurnal16

20

24

28

32

36

Red

uctio

n fr

om B

asel

ine

(%) LBN 0.024% Timolol 0.5%

32.0 32.230.4

32.0

28.427.5

25.3

27.6

94

*P≤0.001 vs. timololCFB = change from baseline


A greater proportion of subjects treated with LBN 0.024% reached target IOP.

Secondary efficacy endpoint: Response rates (ITT population)

0

10

20

30

40Pe

rcen

t of S

ubje

cts

LBN 0.024%Timolol 0.5%

*

*

Mean IOP 18 mm Hgat ALL 9 assessments

% CFB 25%at ALL 9 assessments

20.2

11.2

32.9

19.0

Ocular TEAEs occurring in ≥ 1.0% of study eyes in any treatment group (Safety population)


The majority (>99.5%) of ocular TEAEs were mild or moderate in severity and occurred at a slightly higher frequency with LBN.

There were no non-ocular TEAEs occurring in ≥1.5% of subjects in any treatment group. Vital signs, ocular signs, and BCVA were comparable between treatment groups.

LBN 0.024% (N=560)n (%)

Timolol 0.5% (N=270)n (%)

≥1 ocular TEAE 104 (18.6) 34 (12.6)≥1 treatment-related ocular TEAE 95 (17.0) 30 (11.1)Eye Disorders

Conjunctival Hyperemia 33 (5.9) 3 (1.1)Eye irritation 31 (5.5) 9 (3.3)Eye pain 20 (3.6) 8 (3.0) Ocular hyperemia 9 (1.6) 2 (0.7)Dry eye 6 (1.1) 2 (0.7)Foreign body sensation 6 (1.1) 0 (0.0)Vision blurred 5 (0.9) 4 (1.5)

General disorders and instillation site reactionsInstillation site pain 7 (1.3) 2 (0.7)

Incidence of conjunctival hyperemia per investigator assessment (Safety population)

96

Conjunctival Hyperemia (%)

LBN 0.024% Timolol 0.5%

AnyModerate/

Severe AnyModerate/

Severe

Baseline 38.8 4.3 41.1 3.3

Week 2 49.1 7.9 39.0 0.7

Week 6 47.5 9.7 36.1 3.4

Month 3 45.0 6.8 35.8 2.7LBN = latanoprostene bunodData as observed

Investigators reported similar rates of conjunctival hyperemia between treatment groups, but with a greater proportion of subjects rated as having moderate/severe hyperemia in the LBN group.


Summary and Conclusions LBN 0.024% QD in the evening was effective in reducing IOP in subjects with OAG or OHT with significantly greater IOP-lowering activity compared to timolol 0.5% BID.

• IOP lowering of 7.5 to 9.1 mm Hg from baseline.• Statistically greater IOP lowering >1 mm Hg vs. timolol.• Statistically greater proportion of subjects reached target IOP vs. timolol.

No significant safety findings during the 3 months of double-masked treatment

• Safety findings consistent with PGAs

Thank you!

Questions?

1. What were the efficacy findings for the individual studies?

2. Efficacy vs. latanoprost

3. Why did subjects on Timolol do so well?

Medical Research and Materiel CommandMedical Research and Materiel CommandU.S. Army Aeromedical Research LaboratoryU.S. Army Aeromedical Research LaboratoryFort Rucker, AlabamaFort Rucker, Alabama

Validation Study of Visual Objectives Biomarkers for Acute Mild Traumatic Brain Injury

LTC Jose E. Capó-Aponte, OD, PhD, FAAO

Department of Optometry Womack Army Medical Center, Fort Bragg, NC

UNCLASSIFIED


Disclaimer The views, opinions, and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy, or decision, unless so designated by other

official documentation. The authors have no financial interest on any of the products included in this study.

UNCLASSIFIED

Funded by US Army Medical Research and Materiel Command (USAMRMC), FY13 Department of Defense Army Rapid Innovation Fund Research Program of the Office of the Congressionally Directed Medical Research Programs (CDMRP). Award # W81XWH-14-C-0048.

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UNCLASSIFIED

• The DOD reported that over 340,000 cases of traumatic brain injury (TBI) were confirmed since 2000, with mild TBI (mTBI) accounting for 82.5%.

• The diagnosis of mTBI has been a challenge for the military primarily because: lack of objective assessment tools; overlap of symptoms in co-morbid conditions such as post-traumatic stress disorder (PTSD); interpretation of signs and symptoms by healthcare providers relies on self-reported symptoms from the injured Warfighters.

• Prompt and accurate diagnosis and management of mTBI generally increases an individual's prognosis for neurological recovery and safe return to duty (RTD).

• Premature RTD places Warfighters at greater risk of disability if they suffer an additional concussive trauma.

• Consequently, there is a quest for objective markers (e.g., protein, imaging, cognitive, neurosensory) to objectively diagnose Warfighters with mTBI/concussion.

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Introduction


UNCLASSIFIED

Gaps • Lack of objective markers (e.g., protein, imaging, cognitive, neurosensory) to objectively diagnose Warfighters with mTBI/concussion.• Ideal tool must be: accurate, quick to perform, non-invasive, causes no discomfort or risk to patient, minimal training, deployable, and

low cost.• Valid objective markers are particularly important in the field to assist deployed clinicians to make an accurate determination of fit-for-

duty (FFD)/RTD or evacuation.

Objectives

4

• Since approximately 30 areas of the brain, and 7 of the 12 cranial nerves deal with vision, it is not unexpected that the patient with TBI may manifest a host of visual problems, such as pupillary deficit, visual processing delays, and impaired oculomotor tracking and related oculomotor-based reading dysfunctions.

• This study investigates pupillometry, version (i.e., saccades) and vergence (i.e., convergence) eye movements as potential biomarkers for acute mTBI.

• The study included 3 eye procedures and 1 visual symptoms questionnaire• 10 min test battery.

Introduction


UNCLASSIFIED

• Case-Control Correlational • 200 AD military personnel

– Age ranged from 19 to 44 years; Mean age 26.31±5.81 years• 100 acute mTBI: 87 males & 13 females

– Medically documented mTBI/concussion during the acute phase (≤ 72 hrs) » ≤ 30 min Loss of Consciousness» ≤ 24 hrs Post-Traumatic Amnesia» ≤ 24 hrs Alteration of Mental State» Glasgow Coma Scale score (13 – 15)» Normal structural brain imaging

• 100 age-matched Non-TBI; 79 males & 21 females

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Methods: Design


UNCLASSIFIED

6

NeurOptics PLR-200Hand-held, easy to use, quick, deployable, objective,

non-invasive, requires no specialized training and causes no added discomfort or risk to the patient.

• Monocular Infrared pupillometer under mesoscopic (dim) conditions (~3 cd/m²).

• Subject fixated with the non-tested eye on a distance target (10 ft).

• Stimulus: 180 µW light for 185 msec.

• 8 pupillary light reflex (PLRs) were recorded twice in the right eye and then twice in the left, alternationg between eyes with an interval of about 10 seconds between recording.

Methods: Pupillometry


UNCLASSIFIED

7

1) Max. Pupil Diameter2) Min. Pupil Diameter3) % of Constriction 4) Constriction Latency5) Avg. Constriction Velocity6) Max. Constriction Velocity 7) Avg. Dilation Velocity 8) 75% Recovery of Dilation

Methods: Pupillometry


UNCLASSIFIED

8

• Near Point Rule was used to examine NPC• 20/30 Snellen single letter stimulus. • Repeated 2X

Methods: Near Point Convergence


UNCLASSIFIED

9

Figure A2. The King-Devick Card(s). The first card (top left) is the demonstration card, and subsequent cards are test I, II and IIII, respectively.

Eye movement/version test: Subject is asked to read numbers aloud while being timed. Speed and accuracy is emphasized.

Methods: King-Devick Test


UNCLASSIFIED

Convergence Insufficiency Symptoms Survey

• Score based on scale: always (4) frequently (3) sometimes (2) rarely (1) never (0)

• Passing score ≤20

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Methods: CISS


UNCLASSIFIED

11

Results: Maximum Diameter

OD: P = 0.121C: 5.99±0.78M: 5.88±0.95

OS: P = 0.171C: 5.95±0.73M: 5.78±0.98


UNCLASSIFIED

12

Results: Minimum Diameter

OD: P = 0.431C: 4.05±0.66M: 3.97±0.88

OS: P = 0.306C: 3.99±0.62M: 3.88±0.77


UNCLASSIFIED

Results: % of Constriction

OD: P = 0.188C: 33.08±3.94M: 32.30±4.68

OS: P = 0.719C: 33.30±4.12M: 33.09±4.79

13


UNCLASSIFIED

14

Results: Constriction Latency

OD: P = 0.259C: 219.4±21.67M: 215.9±22.17

OS: P = 0.108C: 218.5±17.94M: 213.8±22.45


UNCLASSIFIED

15

Results: Avg Constriction Velocity

OS: *P < 0.0001C: 4.09±0.55M: 3.68±0.79

OD: *P < 0.0001C: 4.01±0.56M: 3.63±0.77


UNCLASSIFIED

16

Results: Max Constriction Velocity

OD: P = 0.423C: 5.27±0.73M: 5.18±0.82

OS: P = 0.509C: 5.37±0.70M: 5.29±0.81


UNCLASSIFIED

17

Results: Avg Dilation Velocity

OS: *P < 0.0001C: 0.97±0.22M: 0.62±0.28

OD: *P < 0.0001C: 0.91±0.22M: 0.62±0.27


UNCLASSIFIED

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Results: 75% Dilation Recovery Time

OS: *P < 0.0001C: 2.54±0.66M: 4.03±1.11

OD: *P < 0.0001C: 2.65±0.63M: 3.97±1.09


UNCLASSIFIED

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*P < 0.0001C: 8.18±2.15M: 13.24±8.07

Results: Near Point of Convergence

(Objective + Subjective)


UNCLASSIFIED

(Subjective)

20

*P < 0.0001C: 44.24±7.74M: 59.20±19.06

Results: King-Devick Test


UNCLASSIFIED

21

*P < 0.0001C: 8.82±7.42M: 24.76±12.06

Results: CISS

(Subjective)


UNCLASSIFIED

– All methods proof effective tool to differentiate mTBI Vs. Controls.• Objective component: PLR (i.e., ACV, ADV, T75%) • Objective and Subjective component: NPC• Subjective component: KD test • Good correlation with CISS

– Easily performed by subjects, including mTBI– Easily administered by technicians – Faster (3 min) than conventional oculomotor examination (15 min)– Provide tool to expedite mTBI diagnosis and management

• Delegate to technician/medics– Future Direction

• Develop decision matrix to assist medical personnel make RTD decision

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Discussion


UNCLASSIFIED

– Womack Army Medical Center (WAMC) • Thomas A. Beltran

– Defense and Veterans Brain Injury Center / WAMC• Dr. Wesley R. Cole

– The Geneva Foundation / WAMC• Joseph Y. Dumayas• Dr. Ashley Ballard

– US Army Aeromedical Laboratory • LTC David V. Walsh

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Acknowledgement


UNCLASSIFIEDTitle and Classification

LTC Jose E. Capo-Aponte, O.D., Ph.D., F.A.A.O.

Visual Sciences Branch

WAMCDepartment of Optometry

UNCLASSIFIED


UNCLASSIFIED

References• 1. Defence and Veterans Brain Injury Center (DVBIC), DoD Worldwide Numbers for TBI. 2016. http://www.dvbic.org/dod-worldwide-numbers-tbi. • 2. Marion, D.W., et al., Proceedings of the military mTBI Diagnostics Workshop, St. Pete Beach, August 2010. J Neurotrauma, 2011. 28(4): p. 517-26.• 3. Schmid, K.E. and F.C. Tortella, The diagnosis of traumatic brain injury on the battlefield. Front Neurol, 2012. 3: p. 90. • 4. Hoge, C.W., et al., Mild traumatic brain injury in U.S. Soldiers returning from Iraq. N Engl J Med, 2008. 358(5): p. 453-63.• 5. Schneiderman, A.I., E.R. Braver, and H.K. Kang, Understanding sequelae of injury mechanisms and mild traumatic brain injury incurred during the conflicts in Iraq and Afghanistan: persistent

postconcussive symptoms and posttraumatic stress disorder. Am J Epidemiol, 2008. 167(12): p. 1446-52.• 6. Schmid, K.E. and F.C. Tortella, The diagnosis of traumatic brain injury on the battlefield. Front Neurol, 2012. 3: p. 90. • 7. Katz, D.I. and M.P. Alexander, Traumatic brain injury. Predicting course of recovery and outcome for patients admitted to rehabilitation. Arch Neurol, 1994. 51(7): p. 661-70.• 8.Novack, T.A., et al., Outcome after traumatic brain injury: pathway analysis of contributions from premorbid, injury severity, and recovery variables. Arch Phys Med Rehabil, 2001. 82(3): p. 300-5.• 9. Povlishock, J.T. and D.I. Katz, Update of neuropathology and neurological recovery after traumatic brain injury. J Head Trauma Rehabil, 2005. 20(1): p. 76-94.• 10. Khan, F., I.J. Baguley, and I.D. Cameron, 4: Rehabilitation after traumatic brain injury. Med J Aust, 2003. 178(6): p. 290-5.• 11. Vandiver, V.L., J. Johnson, and C. Christofero-Snider, Supporting employment for adults with acquired brain injury: a conceptual model. J Head Trauma Rehabil, 2003. 18(5): p. 457-63.• 12. Slobounov, S., et al., Differential rate of recovery in athletes after first and second concussion episodes. Neurosurgery, 2007. 61(2): p. 338-44; discussion 344.• 13. Marion, D.W., et al., Proceedings of the military mTBI Diagnostics Workshop, St. Pete Beach, August 2010. J Neurotrauma, 2011. 28(4): p. 517-26.• 14. Chesnut, R.M., et al., The localizing value of asymmetry in pupillary size in severe head injury: relation to lesion type and location. Neurosurgery, 1994. 34(5): p. 840-5; discussion 845-6.

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http://www.dvbic.org/dod-worldwide-numbers-tbi


UNCLASSIFIED

Questions?

• 1: Neuroptics also has a newer version of the monocular pupillometer called NPi-100 that provides a Neurological pupil index (NPi) used in neurocritical patients as indication of brain injury severity. Have you considered using the NPi-100 to determine if the patient has a mild TBI/concussion?

2: Did you look at test-retest repeatability of the pupillometer?

• 3: Almost all articles examining the King-Devick as a side-line tool to determine if an athlete sustained a concussion has a pre-game score to compare to post-injury score. Do you think a pre-injury score is absolutely necessary to make an appropriate concussion assessment?

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