January 9, 2006 January 9, 2006

Clinical Research Methods: Interventional Clinical Research

Steven T. DeKosky, MD

Professor and Chairman, Department of Neurology Director, Alzheimers Disease Research Center University of Pittsburgh Pittsburgh, Pennsylvania USA

Definitions of Translational Research

the clinical application of scientific medical research, from the lab to the bedside, intended to translate knowledge derived from laboratory work (basic research) into clinical applications. Clinical investigation with human subjects (patients or normal volunteers) in which knowledge obtained from basic research with genes, cells, or animals is translated into diagnostic or therapeutic interventions that can be applied to the treatment or prevention of disease or frailty.

Fundamentals of Clinical Trials

A clinical trial is a prospective study assessing the effect and value of intervention(s) vs. control in human subjects Each clinical trial has a PRIMARY question (outcome) There may be multiple SECONDARY outcomes
Trials are not powered to definitely answer most questions about secondary outcomesinterpret with caution Ditto for secondary analyses

Fundamentals of Clinical Trials

The study population must be defined in advance, with clear rationale and eligibility criteria A control group must always be used against which the new intervention can be compared Randomization is the most reliable way to assign participants to the treatment groups

Fundamentals of Clinical Trials

A double blind design is the best way to avoid bias during collection of data
If not possible, single blind and other methods should be utilized

Calculation of sample size should be sufficient to provide adequate power and levels of statistical significance

Fundamentals of Clinical Trials

Relevant BASELINE data should be acquired before initiation of intervention All efforts should be made to collect accurate and consistent data Need plan for assessment, analysis and reporting of adverse effects (AEs) and serious adverse events (SAEs)

Evidence Based Medicine: Levels of Evidence

Class I
1. Randomized double-blind, placebo-controlled trials 2. Meta-analyses of such RDBPC trials

Class II

Observational trials (case-control studies or concurrent

control studies)

Class III

All other controlled trials (including well-defined natural

history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment.

Class IV:

Evidence from uncontrolled studies, case series, case

reports, or expert opinion.

A Real Evidence-Based Rating Real Evidence-Based System

class 0: things I believe
class 0a: things I believe despite the available data

class 1: RCCTs that agree with what I believe class 2: other prospective data class 3: expert opinion class 4: RCCTs that dont agree with what I believe class 5: what you believe that I dont
Modified from Bleck BMJ 2000;321:239

Fundamentals of Clinical Trials

FDA requires evidence of SAFETY and EFFICACY to consider approving medications for prescription use. The process by which medications come to market goes through:
preclinical development dose finding then safety trials exploratory efficacy/safety trials larger scale trials to determine the size and consistency of clinical effects, and develop more safety data

Drug Development Process

Discovery (2 - 10 years)

Pre-clinical Testing Laboratory and animal testing Phase 1- 20-80 healthy volunteers used to determine safety and dosage Phase 2 - 100-300 patient volunteers used to look for efficacy (POC) and side effects Phase 3 - 3,000-5,000 patient volunteers used to monitor adverse reactions to long-term use FDA Review/Approval

Years
0 2 4 6 8 10 12 14 16

Source: PhRMA, based on data from Center for the Study of Drug Development, Tufts University. 1995

How would one use these principles to translate research findings into clinically useful data?

Example: Alzheimers Disease

Treatment Biomarkers for assessment of treatment Prevention trials

Alzheimers Disease
Memory loss Language disturbances Visuospatial deficits Dysexecutive: Impaired judgment, motivation, insight Neuropsychiatric symptoms: depression, anxiety, sleep disturbance psychosis Anatomical/circuitry correlates of these behaviors are largely identified
Alzheimers original patient: Auguste D.

thus change in function over short or long periods is a potential outcome measure

Loss of function is insidious and slow, but predictable:

DSM-IV Criteria for Dementia of the Alzheimer Type (standard ENTRY CRITERIA)
A. Multiple cognitive deficits manifested by both 1. memory loss 2. one or more: aphasia, apraxia, agnosia, decline or impairment of executive function B. A1 and A2 cause severe impairment in social or occupational functioning C. Gradual onset and continuing decline of cognition D. A1 and A2 are not due to other CNS conditions, systemic diseases, or substance induced conditions E. Deficits do not exclusively occur during delirium F. Disturbance is not better accounted for by another Axis I disorder (schizophrenia, MDD)
DSM-IV. APA Press, Washington, D.C. 142-143

NINCDS/ADRDA Criteria for Probable Alzheimers Disease [standard diagnostic criteria]

DEMENTIA established by clinical examination; confirmed by cognitive screening test (MMSE, Blessed) Deficits in TWO or MORE areas of cognition Progressive worsening of memory and other cognitive functions No disturbance of consciousness Onset between 40 and 90, most often after 65 Absence of systemic disorders or other brain diseases that could account for the deficits and progression
McKhann et al. Neurol 1984;34:939-944

Major Pathological Changes in AD

Brain shrinkage (atrophy) Neuritic Plaques
altered metabolism of APP Deposition of beta amyloid

Neurofibrillary Tangles
Cytoskeletal pathology [girders and trusses] Altered metabolism of tau protein

Neuronal death in specific brain regions (why some

regions and not others?) serotonin, norepinephrine, glutamate)

Specific Neurotransmitter deficits (especially ACh,

NeuroFibrillary Tangles & Neuritic Plaques

Inflammatory surround

Compacted amyloid core

Tangle (NFT) & Plaque (NP) Distribution In AD Brain at Autopsy

NFT

NP

S. Arnold, Cortex, 1991

Neurofibrillary Tangle Pathology Progression

Delacourte, et al., Neurology 1999

Amyloid Precursor Protein [APP] Metabolism

NORMAL EXTRACELLULAR
SOLUBLE APP (sAPP) BETA SECRETASE BETA-AMYLOID ALPHA SECRETASE BETAAMYLOID NEURONAL MEMBRANE GAMMA SECRETASE

sAPP

AD

CARBOXY TERMINUS INTRACELLULAR

sAPP
BETA-AMYLOID

Beta Amyloid Metabolism: Removal and Secretase Blockade

EXTRACELLULAR
SOLUBLE APP (sAPP)

sAPP
BETA SECRETASE BETA SECRETASE ALPHA SECRETASE
NEURONAL MEMBRANE

BETAAMYLOID

GAMMA SECRETASE GAMMA SECRETASE CARBOXY TERMINUS

INTRACELLULAR

YY Immunization-induced Y antibodies

BETA-AMYLOID

Alter systemic Equilibrium?

Sequence of A Aggregation & Toxicity

Clearance?

2
? dimer oligomer

Inflammatory cells respond

monomers

Induce oxidative stress? Aid neuronal death?

Fibrillar amyloid

Neuronal dysfunction/ death

1 Secretases 1 APP 2 3

Secretases cut the APP molecule

Use secretase inhibitors

Use aggregation inhibitors (Plaque busters)

Immune system attacks A, leads to Plaque formation, neuronal death

A aggregates, forms fibrils

Anti-inflammatory, antioxidants Growth factors; anti-cell death medicines

Modified from Klunk

Alzheimers Disease Course, Alzheimers Treatment, and Prevention

Intervention Primary Prevention Presymptomatic AD Secondary Prevention Mild Cognitive Impairment Treatment

Clinical State

Normal

AD

Brain AD Brain Moderate to Early Brain No Disease Pathologic Changes Changes Severe No Symptoms No Symptoms Mild Symptoms Impairment State

Disease Progression
National Institute on Aging, USA.

Current Symptomatic Drugs for Alzheimers Disease Alzheimers

Tacrine Donepezil Rivastigmine Galantamine Memantine Cognex Aricept Exelon Reminyl Namenda
Cholinesterase Not used much due inhibition to toxicity Cholinesterase Approved 1996 inhibition Cholinesterase Approved in US in inhibition 2000 Cholinesterase Released Spring inhibition 2001 Glutamate receptor modulation Approved 2004

Change in ADAS-Cog and SingleBlind Withdrawal From Donepezil

-3 Improvement

Mean (SE) Change in ADAS-Cog

-2 -1 0 1 2 3 4 0 6 12 18 24 30 Weeks of Drug Treatment Placebo 10 mg Placebo Decline

Adapted from Rogers SL, Farlow MR, Doody RS, et al. Neurology. 1998;50:136-145.

Secondary Prevention: MCI

Conversion Rate of MCI-Amnestic MCI-Amnestic to Dementia (AD Cooperative Study)

100 90 80 70

Proportion 60 Free of 50 Dementia 40 (%)

30 20 10 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

MCI=mild cognitive impairment.

Follow-up Time (Years)

MCI Trial with Vitamin E and Donepezil

Vitamin E
Memory impairment Alzheimers Disease

Donepezil

Placebo
0 6 12 18 24 30 36

Months

Petersen et al., NEJM, 2005

MCI Trial Endpoints

Primary

Conversion to AD
Cognitive

General ADAS-Cog, MMSE ADAS-Cog, Neuropsychological battery

Functional

CDR, ADCS-ADL, GDS, QOL ADCS-ADL,

Petersen et al., NEJM, 2005

Conversion to AD by Treatment Group

1.0 0.9 0.8

1 yr

2 yr

3 yr

Probability of not 0.7 converting to AD 0.6

0.5 0.4 0

Donepezil Vitamin E Placebo DP P=0.416 EP P=0.912

200 400 600 800 1,000 1,200

Time on MCI study (days)

Petersen et al., NEJM, 2005

CP1157990-7

Survival with P-Value Reference from Pointwise P-Value Z-Test: Donepezil vs Placebo Z-Test:
6 mo
1.0 0.9 0.8

1 yr

Probability 0.7 of not converting 0.6 to AD

0.5 0.4 0 6m 12m 18m P=0.004 P=0.04

Donepezil Placebo

24m

30m

36m

Time on MCI study (days) Petersen et al., NEJM, 2005

MCI Therapeutic Trials

Medication
Donepezil & Vitamin E Rivastigmine Rofecoxib Galantamine Galantamine Piracetam

Company
ADCS; medication from Pfizer Novartis Merck Janssen [INT-11] Janssen [INT-18] UCB

N & Study Duration

Outcome
No effect of vitamin E; slight slowing with Donepezil

N = 769 3 yr

N = 1200 Conversion to AD 4 yr N = 1200 Conversion to AD 4 yr 780 N = 780 2 yr N = 780 1 yr Rate of change & MRI Symptom progression Rate of change

Strategies for Future Therapy

Symptomatic improvement (cognitive and behavioral)

Non-specific therapies
Antioxidants Anti-inflammatory agents Estrogen, others

Specific therapies:
Anti-amyloid therapy Anti-neurofibrillary tangle strategies Neurotrophins (growth factors)

Amyloid-specific intervention strategies Amyloid-specific

gamma secretase inhibitors (in phase 1) beta secretase inhibitors (preclinical) alpha secretase enhancers (preclinical) accelerated clearance of beta amyloid (e.g., immunization or passive immunization)
AAB-001/Elan; others

Statins to lower levels of synthesized beta amyloid 2 studies underway in US: simvastatin, atorvastatin block amyloid aggregation (plaque busters)
Alzhemed

Selective amyloid 1-42 lowering agents (SALA) Myriad MPC-7869 / R-flurbiprofen

Amyloid immunization
If immunized from early life, mice with the human APP gene mutation do not deposit plaques
Schenk et al. Nature. 1999.

Brain inflammation in immunization subject On MRI scan

Nicoll, et al. Nature Medicine, 2003

Number of plaques in brain regions

Plaques in untreated AD Subjects

Plaques in AD Patients

Plaques in Immunized Subject

Nicoll et al., 2003

PIB PET in AD and Control

Prevalence of Mild, Moderate/Severe and Total Cases of AD: 2000-2050 2000-2050

12 10 8 6 4 2 0
2000 2010 2020 2030 2040 2050

Mild Mod/Severe

Number of Cases (in millions)

Sloane, et al., Ann. Rev. Public Health 2002. 23:21331

Effect of age: The prevalence of AD doubles in every 5 year epoch from age 65 to 90. Prevalence at 85 approaches 40%

Natural history of dementia

Level of function

dementia

Death 8-12 years

Postponement
Level of function

dementia

Death 8-12 years

Effects of Delay of Onset of Disease on Prevalence of Dementia

Delay (years) 0 .5 1 2 5 4 2 0 2037 2047 Year 8 6 U.S. Prevalence of AD (millions)

1997

2017 2027 2007

5 years of delay of onset equals a 50% decrease in prevalence

Brookheimer et al. Am J Pub Health. 1998;88:1337-1342.

Trade-offs in Developing Trade-offs Prevention Medications

Pressure toward development Safety Effectiveness Ease of use Prior success with similar strategy Costs Side effects Toxicity Risk Pressure against development

For Pharma, issue of how long they can hold use rights after proving proving the medication is effective

Current Prevention Trials

Study ADAPT Alzheimers Disease Antiinflammatory Prevention Trial GEM Ginkgo biloba in Evaluation of Memory PreADVISE Add-on to SELECT prostate cancer prevention trial GUIDAGE 14 sites in France PHSII Physicians Health Study beta-carotene, folic acid, vitamin E Vitamin E, selenium Agent(s) Naproxen, Celecoxib Comment >age 70, NO MCI >2600 subjects; + FHx Treatment halted; Follow-up ongoing

Ginkgo biloba

>age 75; MCI or normal >3000 subjects Recruitment complete Mean age 62 10,000 males: recruiting

Ginkgo biloba

>age 70 2600 subjects

Subjective memory complaint

>age 65 >10,000 Cognitive assessments by telephone; meds by mail

ADCS Meeting Sunday, April 25, 2004 San Francisco, CA

Ginkgo biloba in Dementia and Alzheimers Disease: The Ginkgo in Evaluation of Memory (GEM) Study

Steven T. De Kosky, M.D. Professor and Chair Department of Neurology Director, Alzheimers Disease Research Center University of Pittsburgh Pittsburgh, Pennsylvania, USA

Ginkgo biloba
Dates back 200 million years (a living fossil Charles Darwin) Leaf is the major source of extracts Few side effects; well tolerated Extracts differ in their purity or amount of the Ginkgo compounds

Why study Ginkgo biloba in dementia?

Antioxidant properties of several of its components Flavones, ginkaloids Slight effects on platelet adhesion Possible effects on amyloid aggregation (in vitro) Many studies and claims Many people take it; preparations vary in purity and amount U.S. expenditures for Ginkgo over $200 million/year

Sample Size and Power (N=3000)

Hazard Ratio Power # Ginkgo Events # Placebo Events

.65 .70 .75 .80

.99 .96 .86 .66

172 184 196 209

255 255 255 255

Based on estimated 4% dementia and 6% all-cause mortality per year (2-tailed probability of a Type I error at 0.05), the study will have a power of 96% to detect a 30% reduction in the incidence of dementia in treatment compared to control group.

Outcome Measures:
Primary Outcome:
incidence of dementia (AD)

Secondary Outcomes:
Slow cognitive decline
in normal elderly, from normal to MCI, from MCI to dementia

Decrease rate of functional disability Reduce incidence of cardiovascular and peripheral vascular disease Decrease mortality

GEM Study Methods

Double blind, placebo controlled, parallel design 3000 subjects 240 mg./day of EGb761, in two divided doses, followed for 5 years
Age 75 and above Either normal cognition or MCI (ONE domain impaired below cutoff) N = 3072 final recruitment, completed May 2002

Cognitive & medical examinations every 6 months Dementia Adjudicated by Consensus Committee Vascular events Adjudicated by CHS Committee Total cost approximately $24,000,000and growing
Univ. Pittsburgh, Univ. California-Davis

Involves

Johns Hopkins, Wake Forest Univ. Univ. Washington, Univ. of Vermont

P re s c re e n

Eligibility & Screening Strategies

T e le p h o n e In te r v ie w fo r C o g n itiv e S ta tu s (T IC S ) (C H S /n o n -C H S s u b je c ts )

No

Pass?
Yes

E x c lu d e

S c h e d u le S c r e e n i n g

S c r e e n in g V i s it

O b ta in C o n s e n t; 3 M S E o n S u b je c t, D Q w ith P r o x y

3MSE<80 A b n o rm a l D Q

3MSE<80 N o rm a l D Q

3MSE>80 A b n o rm a l D Q

3MSE>80 N o rm a l D Q

E x c lu d e

N e u ro p s y c h o lo g ic a l te s tin g

N o rm a l o r M C I
V ita l S ig n s B lo o d s d r a w n C E S -D CDR M e d i c a l H is to r y C u r r e n t M e d ic a t io n s R e v ie w A D L / IA D L

D e m e n tia

B lo o d T e s t s CBC P la t e le ts LFTs In fla m M a r k e r s D N A S to r a g e ( n o n s u b je c ts )

E x c lu d e

B12 TSH C r e a t in in e -C H S

M a in N e u r o p s y c h o l o g ic a l B a tt e r y : N e w A d u lt R e a d in g T e s t - A m e r . V e r s io n R a v e n s C o lo u r e d P r o g r e s s i v e M a t r ic e s C a lif o r n ia V e r b a l L e a r n in g T e s t R e y - O s t e r r ie th C o m p le x F ig u r e ( M o d if ie d ) W A IS - R B lo c k D e s ig n ( M o d if ie d ) B o s t o n N a m in g T e s t ( 3 0 - it e m v e r s io n ) W o r d G e n e r a ti o n T r a ilm a k in g A & B S tr o o p D ig it S p a n M M SE and 3M SE * C H S p a r tic ip a n t s d o n o t g e t R a v e n o r A M N A R T a g a in

B a s e lin e V i s it

A D A S -c o g P h y s ic a l E x a m in a tio n N e u r o lo g ic a l E x a m in a t io n ECG V it a l S ig n s A n k le /A r m B lo o d P r e s s u r e s ( A B Is ) S y m p t o m a n d H e a lt h H a b its Q u e s ti o n n a ir e C u rre n t M e d s

R A N D O M IZ A T I O N
A d h e r e n c e C o u n s e li n g & D is p e n s e M e d ic a t i o n S c h e d u le fo r 6 m o n t h v is it

Neuropsychological and Neurological Assessment and Dementia Diagnosis

3MSE CDR ADAS-cog

No NORMAL? Yes

Schedule another visit for long neuropsychological battery

Return in 6 months for next scheduled exam

Yes Evidence of Dementia? No

Full Neurological Exam

If MCI, continue in study; conversion noted in database

Dx: Demented or MCI

Local Adjudication of diagnosis

Notify Site

Adjudicate Dementia Diagnosis

Cognitive Disorders Classification Committee

Cognitive Diagnostic Center

Confirm Dementia Endpoint

Cognitive Screening Scores of Participants at Baseline

Females Males Total Cognitive Score (Number of Participants)**** N or Mean (% or S.D.) (1,419) N or Mean (% or S.D.) (1,653) N or Mean (% or S.D.) (3,072)

3MSE Score (0-100) ADAS - Cog

93.8 ( 4.6) 6.0 ( 2.7)

93.0 ( 4.7) 6.8 ( 2.7)

93.3 ( 4.7)* 6.5 ( 2.7)*

Clinical Dementia Rating (CDR) 0.0 867 (62.2) 0.5 547 (38.6) *** Significant difference between genders,0.2) 1.0 3 ( p < .05

975 (59.1) 666 (40.4) 9 ( 0.5)

1842 (60.1) 1213 (39.6) 12 ( 0.4)

Real World Problems in Studies

Healthy cohort effect
People who volunteer for prevention trials are healthier than average Conversion rates are higher in population studies than in treatment trials, especially in large scale community trials

Power calculations probably underestimate

Differential dropout of subjects who are beginning to decline Cohort that volunteers is healthier and usually better educated Studies will be either longer or larger or both GEM study is an example

Treatment Trial Issues

Primary care doctor may treat at familys complaint or demand and beat the investigators to diagnosis or treatment (problem for both MCI and prevention trials) GEM: watching decline into MCI, waiting for conversion to AD; local doctor starts medication WHIMS:

subjects dropped out significantly: if no follow up, underestimate dementia MMSE improved over time in the cohort; training/learning effect

Course, Prevention, Treatment Strategies

Clinical State
Strategies

Alzheimers Disease: Alzheimers

Presymptomatic AD

Normal

Mild Cognitive Impairment

Stimulate Memory; Slow progression

AD
Treat cognition Treat behaviors Slow progression

Identify at-risk Prevent or Delay Prevent AD Emergence Of Symptoms

NSAIDs Antioxidants Statins Gingko biloba Estrogen NSAIDs Antioxidants Statins Ginkgo biloba Estrogen

Treatment

Secretase inhibitors Immunother.

Secretase inhibitors Immunother.

NSAIDs NSAIDs Antioxidants Antioxidants Statins Statins Ginkgo biloba Ginkgo biloba AChE AChE Inhibitors Inhibitors Estrogen Estrogen/Prg. Memantine Memantine AMPAkines AMPAKines PD4 Inhibitors PD4 Inhibitors Secretase Secretase inhibitors inhibitors Immunother. Immunother.