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

Pre reve venti ntion

• n Tr

Trial als in s in Ol Olde der r Per erso sons: ns: des esign gn de deci cisi sion

• ns

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

• ver
• 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

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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

• tene

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

• up
• 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

• mes
• Surrogate markers

– PEPI and WHI

• Composite outcomes

– How to weigh individual outcomes, especially if they vary

TA TAME ME Ou Outc tcome

• me Co

Cons nsiderations iderations

• Primary outcome: composite (CVD,

Cancer, MCI/Dementia, Mortality)

EN ENRGISE RGISE Ou Outc tcome

• me

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

• utcome 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

• pulation

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