LB ClinTrials

CLINICAL CLINICAL TRIALS IITRIALS IILars Berglund, M.D., Ph.D.Lars Berglund, M.D., Ph.D.

CRISP (Clinical Research Investigator CRISP (Clinical Research Investigator Services Program)Services Program)

U.C. Davis School of MedicineU.C. Davis School of Medicine

Clinical TrialsClinical Trials

ObjectivesObjectives::Practical aspects on how to succeed Practical aspects on how to succeed with a trialwith a trialAlternative study designsAlternative study designs


RecruitmentRecruitment::A key factor – no results without participants.A key factor – no results without participants.

Balance between being too specific or too Balance between being too specific or too diffuse – risk of having too narrow diffuse – risk of having too narrow inclusion/exclusion criteria versus inclusion/exclusion criteria versus introduction of confoundersintroduction of confounders

It’s not entirely your study – best if participants It’s not entirely your study – best if participants are genuinely interested in the studyare genuinely interested in the study


Run-in periodRun-in periodPro:Pro:Provides stabilization and baselineProvides stabilization and baselineTests endurance/reliability of subjectsTests endurance/reliability of subjectsCon:Con:Can be perceived as too demandingCan be perceived as too demanding


It all comes down to . . .It all comes down to . . .Making study participants stakeholdersMaking study participants stakeholdersProtocol as simple to follow as possible Protocol as simple to follow as possible

– refrain from designing “the perfect – refrain from designing “the perfect study”study”

Developing a good contact between Developing a good contact between participants and study personnelparticipants and study personnel

Team spirit Team spirit


Outcome variablesOutcome variables1. Clinical outcomes/endpoints (mortality, 1. Clinical outcomes/endpoints (mortality, admissions, verified disease)admissions, verified disease)2. Surrogate outcomes2. Surrogate outcomes

(risk factors, e.g. LDL chol, CRP, bone density) – (risk factors, e.g. LDL chol, CRP, bone density) – leap of faith as changes in surrogate outcomes leap of faith as changes in surrogate outcomes assumed to predict clinical outcomes.assumed to predict clinical outcomes.

Usually power and cost issues. Usually power and cost issues.


EndpointsEndpointsBalance between being too ambitious or too Balance between being too ambitious or too

conservative – a bit of common sense (“The conservative – a bit of common sense (“The O’Connor situation”).O’Connor situation”).

Focus on a single or a limited number of pre-Focus on a single or a limited number of pre-specified endpointsspecified endpoints

Just because you can measure 15 variables Just because you can measure 15 variables doesn’t necessarily mean that a statistically doesn’t necessarily mean that a statistically significant finding in any of these is clinically significant finding in any of these is clinically meaningfulmeaningful

Primary vs secondary endpointsPrimary vs secondary endpoints


MonitoringMonitoringAdverse eventsAdverse eventsSafety concerns – grounds to stop a Safety concerns – grounds to stop a study? study? For small trials investigators monitor For small trials investigators monitor adverse events, large trials have Data and adverse events, large trials have Data and Safety Monitoring Boards (DSMB’s)Safety Monitoring Boards (DSMB’s)Every GCRC study needs a Data and Every GCRC study needs a Data and Safety Monitoring Plan (DSMP) Safety Monitoring Plan (DSMP)


Examples of early termination of studies:Examples of early termination of studies:

CARET Study (Beta carotene and alpha tocopherol CARET Study (Beta carotene and alpha tocopherol study) – unanticipated CVD risksstudy) – unanticipated CVD risks

Physician’s Health Study – benefit from aspirinPhysician’s Health Study – benefit from aspirin

CARDS (Collaborative Atorvastatin Diabetes Study) CARDS (Collaborative Atorvastatin Diabetes Study) – benefit of atorvastatin for CVD in type II – benefit of atorvastatin for CVD in type II diabetesdiabetes


Clinical trial phasesClinical trial phasesPhase I – safety test in volunteersPhase I – safety test in volunteersPhase II – small randomized, blinded study Phase II – small randomized, blinded study

to test tolerability and efficacy on to test tolerability and efficacy on surrogate outcomessurrogate outcomes

Phase III – large, randomized, blinded trial to Phase III – large, randomized, blinded trial to test clinical outcometest clinical outcome

Phase IV – post-marketing study to assess Phase IV – post-marketing study to assess side effects and/or additional usesside effects and/or additional uses


Alternative designsAlternative designsFactorial design – two questions asked, examples Factorial design – two questions asked, examples Physicians Health Study (aspirin and beta-Physicians Health Study (aspirin and beta-carotene), Heart Protection Study (simvastatin and carotene), Heart Protection Study (simvastatin and vitamins)vitamins)Time series study – subjects studied twice (no Time series study – subjects studied twice (no control group, could be affected by learning trends, control group, could be affected by learning trends, secular trends – time of year, regression to the secular trends – time of year, regression to the mean)mean)

Cross-over design – “wash-out period”Cross-over design – “wash-out period”


Examples of studies and practical Examples of studies and practical problems:problems:

1.1. Program project dominated by Program project dominated by basic science with one clinical basic science with one clinical componentcomponent

2.2. Small investigator-initiated studySmall investigator-initiated study3.3. Large, multicenter NIH-sponsored Large, multicenter NIH-sponsored

studystudy


1. 1. NIH: Diabetes and accelerated vascular NIH: Diabetes and accelerated vascular disease (program project)disease (program project)

Clinical project: Atherogenic TG-rich lipoproteins Clinical project: Atherogenic TG-rich lipoproteins in diabetesin diabetes

Focus: Postprandial response in relation to Focus: Postprandial response in relation to coronary artery disease – would postprandial coronary artery disease – would postprandial response be associated with presence of response be associated with presence of coronary artery disease?coronary artery disease?


Program project dominated by basic science Program project dominated by basic science with one clinical component:with one clinical component:

Postprandial study in diabetic patients with Postprandial study in diabetic patients with and without coronary artery diseaseand without coronary artery disease

Design:Design:Measurement of blood lipids and endothelial Measurement of blood lipids and endothelial

reactivity after a fat-rich high-calorie mealreactivity after a fat-rich high-calorie meal


Problems:Problems:

• Inclusion/exclusion criteriaInclusion/exclusion criteria• Safety parameters (risk of too high TG, Safety parameters (risk of too high TG,

hypo/hyperglycemia)hypo/hyperglycemia)• Optimal design – relation of fat meal to Optimal design – relation of fat meal to

endothelial flow measurementsendothelial flow measurements


Inclusion/exclusion criteria:

How to rule out coronary artery disease in How to rule out coronary artery disease in patients with diabetes?patients with diabetes?

Initial approach: Negative angiograms within Initial approach: Negative angiograms within 1 yr of recruitment - Recruitment problems1 yr of recruitment - Recruitment problems

Modified: Within 2 yrs of recruitmentModified: Within 2 yrs of recruitmentModified: Negative thallium exercise testModified: Negative thallium exercise test


Safety parameters:

High TG:High TG:Patients with DM have commonly hyperTG – risk for Patients with DM have commonly hyperTG – risk for

very high TG during fat load and potential risk for very high TG during fat load and potential risk for pancreatitis – need to screen for baseline pancreatitis – need to screen for baseline parametersparameters

Hyper-hypoglycemia: Hyper-hypoglycemia: Patients fasting following fat load – measure fasting Patients fasting following fat load – measure fasting

glucose at start of studyglucose at start of study


Optimal design:

Time involved – 10 hr follow-up neededTime involved – 10 hr follow-up needed

Need for endothelial reactivity measurement Need for endothelial reactivity measurement at baseline and at expected TG peakat baseline and at expected TG peak

How to ensure a smooth study for each How to ensure a smooth study for each patient? patient?


2. Small investigator-initiated study:2. Small investigator-initiated study:Influence of estrogen on lipoprotein(a) in Influence of estrogen on lipoprotein(a) in

postmenopausal womenpostmenopausal womenIssues: Issues: 1.1. Define length of “wash-out” phaseDefine length of “wash-out” phase2.2. Practical aspects: Placebo, who will Practical aspects: Placebo, who will

ensure blinding, randomization in blocksensure blinding, randomization in blocks3.3. How to deal with subgroups (ethnic, How to deal with subgroups (ethnic,

Lp(a) characteristics)Lp(a) characteristics)


3. 3. Large, multicenter NIH-sponsored Large, multicenter NIH-sponsored study (4 research centers)study (4 research centers)

Dietary effects on lipoproteins and Dietary effects on lipoproteins and thrombogenic activities (DELTA)thrombogenic activities (DELTA)

Design: Randomized, double-blind Design: Randomized, double-blind cross-over study to test cross-over study to test carbohydrates vs monounsaturated carbohydrates vs monounsaturated fat as replacement for saturated fat fat as replacement for saturated fat in insulin-resistant subjects in insulin-resistant subjects


Dietary effects on lipoproteins and Dietary effects on lipoproteins and thrombogenic activities (DELTA)thrombogenic activities (DELTA)

Challenges:Challenges:• Recruitment retainment (meals provided and Recruitment retainment (meals provided and

consumed on site)consumed on site)• Meal design – same menus for Minnesota and Meal design – same menus for Minnesota and

LouisianaLouisiana• Weight maintenance, physical exerciseWeight maintenance, physical exercise• Wash-out periodWash-out period• Between-center variability – harmonize teamsBetween-center variability – harmonize teams


What resources do you need?What resources do you need?Good teamwork (PI and staff)Good teamwork (PI and staff)Recruitment baseRecruitment baseInfrastructure (stats, databases, IRB Infrastructure (stats, databases, IRB

protocols, location)protocols, location)


Resources at UC Davis:Resources at UC Davis:• CRISPCRISP• GCRCGCRC

LB ClinTrials

Documents

Transcript of LB ClinTrials