youre bound to regret David B. Reuben, MD Archstone Foundation - PowerPoint PPT Presentation

Pre reve venti ntion on Tr Trial als in s in Ol Olde der r Per erso sons: ns: des esign gn de deci cisi sion ons s you’re bound to regret David B. Reuben, MD Archstone Foundation Chair and Professor David Geffen School of Medicine at UCLA

• You can choose this approach or that approach. Either way, you’ll be sorry. – Byron William (Bill) Brown, Stanford biostatistician

Wh What at we we wi will ll cover over • Who? – In and Out: Internal validity vs generalizability • What? – Choice of intervention – Potential for AEs – Control group • Outcomes • General issues

Wh Who • What is the age group? – Younger (e.g., mid-life) to affect pathways earlier before irreversible age-related damage – Older because relevant outcome measures would be expected to occur sooner • What are the inclusionary criteria? – Is this a real population?

TA TAME ME-Inclu Inclusion sion Cri Criteria teria • 3,000 volunteers aged 65 to 80 years – Primary prevention (TMS; gait speed < 1m/s) – Secondary • CVD (<2 of following: MI, stroke, CHF, PAD, revascularization) • Cancer • MCI

ENRGISE NRGISE Inc nclusion lusion Cri riteria teria • Men and women aged 70 years and older – Self-reported difficulty walking ¼ mile or climbing a flight of stairs – Usual walking speed <1 m/sec, but >0.44 m/sec – Able to walk 400 m – IL-6 >2.5 pg/ml and <10 pg/ml 6

Wh Who • What age group? – Younger (e.g., mid-life) to affect pathways earlier before irreversible age-related damage – Older because relevant outcome measures would be expected to occur earlier • What inclusion criteria? – Is this a real population? • What exclusion criteria? – Is anybody left?

TA TAME ME Ex Exclusions clusions – Type 2 Diabetes (22% of pop 65-74, CDC 2014) – eGFR < 60 (26% of pop 60+ NHANES 2001-2008) – Hospitalization or procedure related to CVD treatment in the past year – Cancer under treatment unless excellent prognosis – Dementia (11% 65+, Alzheimer’s Association) – ADL or IADL disability (26% of 65+, HRS 2008) – Recent weight loss (>5% in the past year) – Limited life expectancy (<5 years) – Inability to provide informed consent

Wh What? at? Th The e In Interv terventions entions • Duration of intervention • Secular trends • Choice of intervention drug – Cheap – Easy to take – No AEs • Known susceptibility (would be an exclusion) • Incident susceptibility (you don’t know about this or it hasn’t happened yet) – Accutane (13-cis retinoic acid) •

Established tablished Saf afe e Dr Drugs ugs • Sal alsala alate te (AKI in anemia study) • Prema emarin rin (Adverse composite in WHI) • Bet eta a Car arote otene ne (Increased lung cancer in prevention trial of those at risk because of smoking or asbestos exposure

TA TAME ME Dr Drug ug Co Considerations nsiderations • Metformin 850 bid vs placebo for 3.5 to 5 y • People taking metformin get IV contrast dye; develop renal impairment with acute conditions, age into it (incident susceptibility) • Rare but important AEs – Metformin: : Lactic acidosis (all patients) • 0.03 cases per 1000 patient years • 0.015 fatal cases per 1000 patient years

ENRGISE NRGISE Dr Drug ug Co Considerations nsiderations • All ARBs are not alike • Losartan costs less but: – Less BP control and slight fall in uric acid – Shorter acting and active metabolite (EXP-3174) – Greater percent (35%) eliminated renally – Highest potential for drug interactions due to CYP P450 • Drug interactions with ω -3 (e.g., warfarin)

Co Control ntrol Gr Grou oup • Standard of care – Based on DPP trial, should pre-diabetic TAME control group participants get metformin? – Based on PREDIMED and FINGER, should TAME intervention and control participants group get Mediterranean diets, exercise, CV RF factor control, and cognitive training? – Based on LIFE, should ENRGISE intervention and control group participants receive an exercise intervention?

Ou Outc tcomes omes • Surrogate markers – PEPI and WHI • Composite outcomes – How to weigh individual outcomes, especially if they vary

TA TAME ME Ou Outc tcome ome Co Cons nsiderations iderations • Primary outcome: composite (CVD, Cancer, MCI/Dementia, Mortality)

EN ENRGISE RGISE Ou Outc tcome ome Co Considerations nsiderations • Primary Outcomes – IL-6 – Walking speed during 400 m walk test • Secondary outcomes – SPPB – Frailty – Grip strength – Isokinetic knee extension strength – Inability to walk 400m (planned primary outcome for the main trial) – Biomarkers of inflammation

Ge Gene neral ral Is Issues sues • Willingness to accept collateral damage • Is there a different threshold for risk of AEs for prevention than treatment of disease? • Need for pilot data • Cost of trial (blackjack tables) • Burden of being in a trial

Co Considerations nsiderations Wh When en Tr Trea eating ting Ge Gene neral ral Pop opulation ulation • What is the importance of the outcome being prevented? • What is prevalence of the outcome being prevented? • What is the magnitude of the effect size? • What are the risks of the treatment?

Ge Gene neral ral Is Issues sues in n Prev revention ention Tr Trials ials • What is the importance of the outcome being prevented? • What is prevalence of the outcome being prevented? • How strong is the linkage between the risk factor and the outcome (attributable risk)? • What is the magnitude of the effect size? • What are the risks of the treatment?

SPRINT RINT Excl xclusion usion Cri Criteria teria • Diabetes mellitus • History of stroke (not CE or stenting) • End stage renal disease (ESRD) • Cardiovascular event or procedure or hospitalization for unstable angina within last 3 months

SPRINT RINT Excl xclusion usion Cri Criteria teria • Symptomatic heart failure within the past 6 months or left ventricular ejection fraction (by any method) < 35% • A medical condition likely to limit survival to less than 3 years, or a cancer diagnosed and treated within the past two years that, in the judgment of clinical study staff, would compromise a participant’s ability to comply with the protocol and complete the trial

SPRINT RINT Excl xclusion usion Cri Criteria teria • Any factors judged by the clinic team to be likely to limit adherence to interventions • Residence in a nursing home. Persons residing in an assisted living or retirement community are eligible if they meet the other criteria.

SPRINT RINT Excl xclusion usion Cri Criteria teria • Clinical diagnosis of dementia, treatment with medications for dementia, or in the judgment of the clinician cognitively unable to follow the protocol • Other medical, psychiatric, or behavioral factors that in the judgment of the Principal Investigator may interfere with study participation or the ability to follow the intervention protocol