Implementation of a Randomized Controlled Trial: A Case Study

1. Implementation of a Randomized Controlled Trial: A Case Study November 4, 2010 Grover C. Gilmore 96 Years of Leadership in Social Justice

2. Objectives What will not be covered. • Theoretical comparison of Randomized Clinical Trial (RCT) design to other research designs. • Tutorial on statistical methods.

3. Objectives What will be covered. • Development of a clinical intervention study from inception to funding and implementation. • Path from “simple” research design to an RCT.

4. Project Therapeutic Effects of Cataract Removal in Alzheimer’s Disease Grant Number: 1R01AG030114 Period of Funding: June 15, 2009 – May 31, 2014 Total Funding: $2,869,861

5. Research Team • PI: Gilmore, G. C. 1 • Co-Investigators Staff • Belkin, J. 2,3 Bielefeld, R. 5 • Debanne, S. 2 Garvey, M. 5 • Lass, J. 2,3 Obrien, A. 4 • Lerner, A. 2,3 Ogrocki, P. 2 • Steinemann, T. 2,4 Reidel, T. 1 • Sami, S. 2 • Consultants Washington, K. 2 • Auchus, A.6 • Singh, A. 2,3 1MSASS, 2 SOM, 3UHCMC, • Trocmé, S. 2,3 4MHMC, 5 ARC-CWRU, 6UMMC

6. Evolution of Research Idea

7. Cataracts • A cataract is a clouding that develops in the crystalline lens of the eye. • Age-related cataracts are responsible for 48% of world blindness. • In the United States, age-related cataracts have been reported in 42% of those between the ages of 52 to 64, 60% of those between the ages 65 and 74,and 91% of those between the ages of 75 and 85. • Cataract surgery is a common, same-day procedure in the USA.

8. Alzheimer’s Disease • Most common form of dementia. Estimated in 2006 to affect 26.6 million people worldwide. • Prevalence for ages 65-74 years is 3%, 75-84 years is 18.7%, 85+ is 47%. • Memory problems are the hallmark of the disease. • There is growing evidence that vision is affected by Alzheimer’s Disease. • However, the vision disorders are not commonly known by physicians.

9. Alzheimer’s Disease and Peripheral Visual Pathology • Eye • Lens b-amyloid is present in lens fiber cells • Aqueous Humor b-amyloid present • Optic Nerve Nerve degeneration • Retina Ganglion cell loss; b-amyloid deposition; reduction in thickness of RNFL • Subcortical Visual Centers • Lateral Geniculate Nucleus (LGN) b-amyloid plaques • Pulvinar b-amyloid plaques • Superior Colliculus b-amyloid plaques & • Neurofibrillary Tangles (NFT)

10. Eye Disease in Alzheimer’s Disease Glaucoma Incidence of disease is 3 times higher in AD samples relative to controls Macular Degeneration Report of significantly higher incidence of ARMD in sample of AD patients No other eye diseases reported to have higher incidence rate in Alzheimer’s disease patients.

11. Vision in Alzheimer’s Disease Acuity Normal for age Color vision Deficits in color discrimination particularly on the blue axis Stereoacuity Deficits in both monocular and binocular depth perception Contrast Sensitivity Deficits in seeing both low and high spatial frequencies Motion Perception Deficit in motion discrimination Evoked responses Deficits in Flash Visual Evoked Potential (FVEP) & Pattern Electroretinogram (PERG, particularly for high temporal frequencies

12. Normal Vision

13. Cataract

14. Alzheimer’s Disease

15. Cataract and Alzheimer’s Disease

16. Is there reason to believe that the improvement of the visual signal will lead to better performance by the patient with Alzheimer’s Disease? YES!

17. Selected Articles Demonstrating the Benefit of Stimulus Enhancement for Alzheimer’s Disease Patients Cronin-Golomb, A., Gilmore, G. C., Neargarder, S., Morrison, S. R., & Laudate, T. M. (2007). Enhanced stimulus strength improves visual cognition in aging and Alzheimer’s disease. Cortex, 43, 952-966. Gilmore, G. C., Cronin-Golomb, A., Neargarder, S. A., & Morrison, S. R. (2005). Enhanced stimulus contrast normalizes visual processing of rapidly presented letters in Alzheimer’s disease. Vision Research, 45, 1013-1020. Gilmore, G. C., Groth, K. E., & Thomas, C. W. (2005). Stimulus contrast and word reading speed in Alzheimer’s disease. Experimental Aging Research, 31, 15-33. Gilmore, G. C., Morrison, S., & Groth, K. (2004). Magnocellular deficit hypothesis in Alzheimer’s disease. In A. Cronin-Golomb & P. R. Hof (Eds.), Interdisciplinary Topics in Gerontology: Vision in Alzheimer’s Disease and Related Disorders, Vol. 34, 173–198, Basel: Karger. Gilmore, G. C., Royer, F. L., Gruhn, J. J., & Esson, M. J. (2004). Symbol-digit substitution and individual differences in visual search ability. Intelligence, 32, 47-64. Cronin-Golomb, A., & Gilmore, G. C. (2003). The role of vision in cognitive dysfunction and enhancement in Alzheimer’s disease. In S. Soraci & K. Murata-Soraci (Eds.), Visual Information Processing (pp. 3-34). Westport, CN: Praeger. Koss, E. & Gilmore, G. C. (1998). Environmental interventions and functional ability of Alzheimer's Disease patients. Research and Practice in Alzheimer’s Disease, 185-191. Gilmore, G. C., Thomas, C. W., Klitz, T., Persanyi, M., & Tomsak, R. (1996). Contrast enhancement eliminates letter identification speed deficits in Alzheimer’s disease. Journal of Clinical Geropsychology, 2, 307-320. Gilmore, G. C. (1995). Stimulus encoding in Alzheimer’s disease: A multichannel view. In P. Allen and A. Bashore (Eds.), Age differences in word and language processing (pp. 199-219). Elsevier Science B.V.

18. Picture Naming • Participants were presented with stimuli with adjusted contrast. • Enhanced • Normal • Degraded • The amount of contrast change was determined by the differences in spatial contrast sensitivity between healthy elderly adults and Alzheimer’s patients

20. Picture NamingAccuracy (%)

21. Genesis of a Research Project • There were four applications before funding was approved. • Alex Auchus was the PI on the first Application. • Grover Gilmore was PI on subsequent applications. • With each application, there were changes in the research design and the size of the budget.

22. Application 1 June, 2005 Specific Aim Primary To determine the effects of cataract removal on visual acuity, spatial contrast sensitivity, visual information processing, independent function and quality of life in patients with Alzheimer’s disease. Research Design Longitudinal Study (12 mos) with One Group AD, visually significant cataracts, intervention (experimental group) Evaluate change in multiple measures from baseline to post-intervention over 12 mos.

23. Application 1 June, 2005 Analysis Plan The primary outcome measure will be change in total ADCS-ADL score between baseline and post-intervention. Changes in spatial contrast sensitivity, VF-14 scores, and QoL-AD scores will be assessed as secondary outcomes. We will gather information on demographic variables (age, gender, race, education) and baseline MMSE scores in order to adjust the results for effects of these potential confounders in the analyses. The primary analysis will be conducted via pairwise comparison for changes in baseline vs. post-intervention ADCS-ADL scores using two-sided, paired t-tests.

24. Application 1 June, 2005 Response to RFA-AG-05-007 on Developing Interventions for Multiple Morbidities Requested Funding $415,250 Period 9/2005 – 9/2007 Result Priority Score: 223 Denied funding Strengths identified included the superb research team and the importance of the topic. Weaknesses included a lack of a control group, paucity of visual function measures, and a confusing statistical plan. Decision by Research Team Revise and submit as an R01 with Gilmore as PI

25. Application 2 June, 2006 Specific Aim Primary To determine the effects of cataract removal on visual acuity, spatial contrast sensitivity, visual information processing, independent function and quality of life in patients with Alzheimer’s disease. Research Design Longitudinal Study (12 mos) with Three Groups Group A: no AD, visually significant cataracts, intervention (disease control) Group B: AD, visually significant cataracts, intervention (experimental group) Group C: AD, visually significant cataracts, no intervention (intervention control)

26. Application 2 June, 2006 Analysis Plan Matching algorithm used to ensure comparability of Intervention group with the three control groups. Mixed ANOVA will be used. Repeated measures comparisons within groups will test the change over time in vision, visual information processing, and quality of life associated with or without the removal of cataracts. Having two control groups will allow us to determine the potentially opposing effects of worsening outcomes attributable to ongoing AD, and improving outcomes attributable to surgical restoration of vision.

27. Application 2 June, 2006 Response to PAR-05-021 on Alzheimer's Disease Pilot Clinical Trials Requested Funding$2,290,328 Period 4/2007 – 3/2011 Result Priority Score: 248, Percentile: 48.4 Denied funding Strengths identified included the focus on an important clinical issue, the well qualified research team, and the use of widely available visual and cognitive assessment tools. Weaknesses included the lack of randomization (RCT), absence of preliminary data, and weak research design description. Decision by Research Team Revise and submit

28. Application 3 June, 2007 Specific Aim Primary To determine the effects of cataract removal on visual acuity, spatial contrast sensitivity, visual information processing, independent function and quality of life in patients with Alzheimer’s disease. Research Design Longitudinal Study (12 mos) with Four Groups Group A: no AD, visually significant cataracts, intervention (disease control) Group B: AD, visually significant cataracts, intervention (experimental group) Group C: AD, visually significant cataracts, no intervention (intervention control) Group D: AD, no significant cataracts, no intervention (cataract and intervention control)

29. Ethical Objections To RCT • For ethical reasons we have decided not to randomly assign patients with cataracts to the intervention and non-intervention groups. • The samples will reflect valid comparison groups that ophthalmologists will encounter in their practice. We chose not to use random assignment for several reasons. • First, all of the potential participants will have come to the study ophthalmologist because of significant vision problems. • Second, asking an individual to postpone treatment may put this individual at risk for negative events that are associated with cataracts, such as falls. • Third, the postponement of surgery by older adults denies them the potential benefits of the surgery for what may be a significant time period in their remaining life. • Finally, there is a practical consideration. If we asked patients to postpone surgery that they are seeking, they will simply leave the study and obtain the surgery from another ophthalmologist. • Opinions supported by two Bioethicists: (Stephen Post, CWRU; Arthur Caplan, Penn). Both strongly agreed with our judgment that it would be unethical to randomly assign patients with AD and seeking cataract removal to the treatment group and to withhold surgery for 12 months from those assigned to the control group.

30. Application 3 June, 2007 Analysis Plan Matching algorithm used to ensure comparability of Intervention group with the three control groups. The proposed analysis is most clearly presented in the context of analysis of variance (ANOVA) techniques for incomplete designs, in particular, a 3-way factorial design, with 2 structural empty cells and 2 empty cells related to the choice of design. The structural empty cells would contain those subjects, with or without AD, that have no cataracts but have surgery. These cells would always be empty since human subjects without cataracts could not have surgery. The approach will also involve the inclusion of covariates (ANCOVA) in order to account for baseline levels of outcome variables and covariates not controlled by the matching procedure.

31. Application 3 June, 2007 Response to PAR-07-142 on Alzheimer's Disease Pilot Clinical Trials Requested Funding$2,713,720 Period 4/2008 – 3/2012 Result Priority Score: 221, Percentile: 43.3 Denied funding Strengths were the research team and the comprehensive analysis plan. Weaknesses included the lack of randomization (RCT); rejected ethics argument. Decision by Research Team Revise and submit; address ethics limitations

32. Application 4 June, 2008 • Specific Aim • Primary • To determine the effects of cataract removal on visual acuity, spatial contrast sensitivity, vision dependent functions, visual information processing, and quality of life in patients with Alzheimer’s disease. • Research Design • Randomized Controlled Trial (RCT) • Random assignment of AD patients • Immediate cataract surgery group • Delayed cataract surgery group • Study partner for each participant • Evaluation for 6 months

33. Application 4 June, 2008 Analysis Plan Primary Aim Differences in the change in visual outcomes (visual acuity, contrast sensitivity and visual function as per VF-14) between the intervention and control group will be assessed using a repeated measures ANOVA model. Once the potential effect of surgery is assessed, and it is seen whether outcomes change over time, the issue of whether outcomes are different for different severity groups (mild or moderate AD, and cataract severity) will be examined. Again, significant effects of severity on outcomes will be assessed by statistical significance of the corresponding coefficients.

34. Application 4 June, 2008 Response to PAR-08-062 on Alzheimer's Disease Pilot Clinical Trials Requested Funding$3,708,053 Period 6/2009 – 5/2014 Result Priority Score: 141, Percentile: 10.8 Funded !!! Strengths are the importance of the problem and the strong research team. Weaknesses may be difficult to enroll AD patients who are seeking cataract removal and are randomized to the delayed surgery group. Decision by Research Team Celebrate and get to work recruiting

35. Study Population • Research Participants (n=210) • Diagnosed with mild to moderate Alzheimer’s Disease (AD) • Bilateral cataracts with acuity ≥ 20/50 • Research Study Partners (n=210) • assure protocol adherence by AD participant • provide information about behavioral symptoms, activities of daily living, and amount of resources used

36. Data Collection Text, chart and/or photo here.

37. ImplementationChallenges • IRB Review at bothUHCAMC and MHMC • Paper forms at UHCAMC, Efile at MHMC • Approval delayed at MHMC until project met staff hiring requirements dictated by IRB • Recruitment • Combating bias in medical community against treating cataracts in AD patients • Perceived burden on caregivers • No partner to assist AD patient

38. Implementation of a Randomized Controlled Trial: A Case Study Grover C. Gilmore