significance of the midas and adcs trials with dha for secondary prevention and treatment of ad

1. Significance of the MIDAS and ADCSTrials with DHA for SecondaryPrevention and Treatment of AD Joseph Quinn, MD Oregon Health and Sciences University Portland, OR Disclosure: Dr. Quinn is named as an inventor on a patent filed by Martek Biosciences on DHA for the treatment of Alzheimer’s disease in ApoE4 negative patients. The patent was filed after data analysis was complete in the ADCS study. Dr. Quinn has waived his rights to royalties.

3. Clinical trials: ADCS trial: 18 month clinical trial in mild to moderate AD, conducted by the NIA-funded Alzheimer’s disease cooperative study. MIDAS study: 6 month clinical trial in healthy elderly with memory complaints, conducted by Martek Biosciences.

4. ADCS protocol design: Study population Probable AD MMSE=14-26 Approved anti-dementia meds (CEIs, memantine) OK Baseline DHA intake = 200 mg/day Intervention Randomized, double blind, placebo controlled trial of 2 g Martek’s algal DHA vs placebo Randomized 60:40 active:placebo Treated for 18 months Outcomes Co-primary outcomes: rate of change on ADAS-cog, CDR-SOB Secondary outcomes: rate of change ADCS-ADL, NPI, QOL, MMSE (MRI and CSF biomarker studies on sub-populations, analysis pending) Recruited 402 subjects Feb-Nov 2007, last visit 5/09

6. ADCS trial: DHA vs placebo at baseline

7. Compliance-plasma DHA

8. Compliance-CSF DHA

9. Co-Primary outcome: ADAS-cog

10. Co-Primary outcome: CDR-SOB

11. Secondary outcome: ADCS-ADL

12. Secondary outcome: NPI

13. Secondary outcome: MMSE

14. Pre-specified sub-group analyses: ADAS result in MMSE above and below median:

15. Pre-specified sub-group analyses: ADAS result in ApoE4 positive and negative

16. Pre-specified sub-group analyses: other outcome measures in ApoE negative subjects:

17. ADAS outcome in E4 negative subjects: “high” vs “low” baseline MMSE(median split):

18. MRI sub-study Invited all MRI-eligible subjects at ADNI sites 170 baseline MRI scans 102 baseline + 18 month suitable for analysis

19. Brain atrophy rates: total brain and ventricle volume

20. ADCS trial summary DHA supplementation increased both plasma and CSF DHA levels. DHA supplementation was well tolerated No DHA treatment effect was seen in the total population on any outcome measure. No DHA effect in milder AD (ie, higher MMSE). In the ApoE negative population, a benefit of DHA treatment was seen on ADAS-cog and MMSE, but no other outcome measure.

21. H1: DHA would improve Cognitive function. Objectives Study Timepoints: Screening, Baseline, 4 weeks Safety, 12 and 24 weeks Efficacy and Safety Population: healthy elderly (>55 yrs) with mild memory impairment Age-related Cognitive Decline-- Older person with objective cognitive decline relative to younger years, but normal function relative to age-related peers Corn/soy oil 50% LA, 25% oleic acid; 9kcal—negligible increase inn Western diet (<10% of dietary fat intake/d) H1: DHA would improve Cognitive function. Objectives Study Timepoints: Screening, Baseline, 4 weeks Safety, 12 and 24 weeks Efficacy and Safety Population: healthy elderly (>55 yrs) with mild memory impairment Age-related Cognitive Decline-- Older person with objective cognitive decline relative to younger years, but normal function relative to age-related peers Corn/soy oil 50% LA, 25% oleic acid; 9kcal—negligible increase inn Western diet (<10% of dietary fat intake/d)

23. GDS 1.3 both grps, over time, p=0.25; alcohol use: 2unit/wk (1 unit=1shot liquor;8 oz.beer) FFQ baseline mean=104 mg DHA/d,both grp; wk24, 112mg/d both grp, p<0.32 MMSE over time p<0.729GDS 1.3 both grps, over time, p=0.25; alcohol use: 2unit/wk (1 unit=1shot liquor;8 oz.beer) FFQ baseline mean=104 mg DHA/d,both grp; wk24, 112mg/d both grp, p<0.32 MMSE over time p<0.729

24. MIDAS-outcome measures Pre-specified primary outcome measures: CANTAB paired associate learning (PAL) CANTAB pattern recognition memory (PRM) Pre-specified secondary outcome measures: CANTAB verbal recognition memory (VRM) CANTAB stockings of london (SOC,executive) CANTAB spatial working memory (SWM) Frequency of forgetting-10 ADCS-ADL Geriatric depression scale

25. MIDAS-outcome measures On the basis of an interim analysis which was pre-specified to evaluate for futility, the CANTAB PRM was dropped as a primary outcome measure.

26. CANTAB® Paired Associate Learning Significantly fewer errors were made on the PAL with DHA supplementation for 6 months versus placebo. No effect of DHA upon the CANTAB pattern recognition memory (PRM) MIDAS – Results Episodic memory-ability to remember recent information and experiences accurately, e.g. recalling a story or where you put your keys VRM Immed. ITT: mean change 0.2 DHA; 0 PBO,diff.0.4+/-0.17, 95% CI (0.1, 0.7) p=0.018; VRM Delayed ITT: mean change 0.3 DHA;0.1 PBO, diff. 0.5+/-0.18, 95%CI (0.1, 0.8) p=0.012 Semantic memory-factual knowledge, e.g. name of the first U.S. President Procedural memory-ability to learn cognitive, behavioral skills, e.g. remembering how to drive a stick shift or ride a bike Working memory-ability to temporarily maintain and use information, e.g. remember a phone number before you dial, or directions to get to a new place Episodic memory-ability to remember recent information and experiences accurately, e.g. recalling a story or where you put your keys VRM Immed. ITT: mean change 0.2 DHA; 0 PBO,diff.0.4+/-0.17, 95% CI (0.1, 0.7) p=0.018; VRM Delayed ITT: mean change 0.3 DHA;0.1 PBO, diff. 0.5+/-0.18, 95%CI (0.1, 0.8) p=0.012 Semantic memory-factual knowledge, e.g. name of the first U.S. President Procedural memory-ability to learn cognitive, behavioral skills, e.g. remembering how to drive a stick shift or ride a bike Working memory-ability to temporarily maintain and use information, e.g. remember a phone number before you dial, or directions to get to a new place

27. Secondary Cognitive Measures CANTAB Verbal Recognition memory test showed significantly more words recognized (immed. & delayed) with DHA, p<0.02 No treatment effects on CANTAB SOC, SWM No treatment effects on MMSE, Geriatric Depression No treatment effects on ADCS-ADL (2 point improvement, both grps, p=0.59) MIDAS – Results Episodic memory-ability to remember recent information and experiences accurately, e.g. recalling a story or where you put your keys VRM Immed. ITT: mean change 0.2 DHA; 0 PBO,diff.0.4+/-0.17, 95% CI (0.1, 0.7) p=0.018; VRM Delayed ITT: mean change 0.3 DHA;0.1 PBO, diff. 0.5+/-0.18, 95%CI (0.1, 0.8) p=0.012 Semantic memory-factual knowledge, e.g. name of the first U.S. President Procedural memory-ability to learn cognitive, behavioral skills, e.g. remembering how to drive a stick shift or ride a bike Working memory-ability to temporarily maintain and use information, e.g. remember a phone number before you dial, or directions to get to a new place Episodic memory-ability to remember recent information and experiences accurately, e.g. recalling a story or where you put your keys VRM Immed. ITT: mean change 0.2 DHA; 0 PBO,diff.0.4+/-0.17, 95% CI (0.1, 0.7) p=0.018; VRM Delayed ITT: mean change 0.3 DHA;0.1 PBO, diff. 0.5+/-0.18, 95%CI (0.1, 0.8) p=0.012 Semantic memory-factual knowledge, e.g. name of the first U.S. President Procedural memory-ability to learn cognitive, behavioral skills, e.g. remembering how to drive a stick shift or ride a bike Working memory-ability to temporarily maintain and use information, e.g. remember a phone number before you dial, or directions to get to a new place

28. MIDAS conclusions: Post hoc analysis suggests some cognitive measures (ie, episodic memory) in healthy elderly are improved with DHA ApoE genotyping was not done in MIDAS

29. ADCS and MIDAS data: significance for standard of care: We can conclude that DHA is not effective for slowing the progression of AD in the overall population. The evidence for an ApoE4 genotype- dependent effect in AD is modest. The MIDAS finding in healthy elderly may be considered post hoc, based on the failure to demonstrate efficacy on both pre-specified endpoints.

30. ADCS and MIDAS datasignificance for future research:

31. What is the significance of the ADCS and MIDAS data? Some investigators have proposed further study of DHA in E4 negative AD subjects and/or in MCI. The ADCS steering committee has concluded that an MCI trial is not justified by the data available at this point.

32. Acknowledgements: ADCS Sites ADCS Coordinating center Operations Monitors Data core Leadership Martek Biosciences NIA (ADCS grant: U01-AG10483) Participating subjects and families