london limitation of clinical trials

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Limitations of Clinical Trials in Sickle CellDisease: A case study of the Multi-centerStudy of Hydroxyurea Trial (MSH) and the

Stroke Prevention Trial (STOP)

Michael R. DeBaun, MD, MPH


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Objectives

Strength of randomized clinical trials

Limitations of clinical trials

Multi-Center Study of Hydroxyurea in Sickle Cell

Anemia (MSH) STOP Trial

Secondary Analysis MSH

Clinical Drift MSH

Summary and Recommendations


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Strengths of Clinical Trials

Sackett, DL. BMJ. 1996 Jan 13;312(7023):71-2


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Limitations of Clinical Trials

Narrow inclusions criteria Over interpretation of secondary analyses

Expensive Cost of MSH ~ $10 million Cost STOP I ~ $12.1 million; STOP II ~ $11 million Silent Infarct Transfsuion Trial~ $18.5 million

Time consuming Length from conception to completion of the trial

Silent Infarction Trial ~15 years


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Multi-Center Study of Hydroxyurea (MSH)(N Engl J Med 1995;332:1317-22.)

HypothesisHypothesis Hydroxyurea willsubstantially reduce the frequency of

painful episodes in adults with Hgb SS


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Multi-Center Study of Hydroxyurea

Inclusion CriteriaInclusion Criteria

minimum of 18 years of age

Only accepted those with Hgb SS

At least 3 painful episodes in the last year No documentation was required

No previous use hydroxyurea


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Methods of the MSH Trial

Randomized trial

299 participants spanning 21 clinics in the U.S. and Canada

Patients were given pre-prepared doses ofhydroxyurea or placebo on a regular basis

Primary endpoint

Pain


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Results of the MSH Study

Pain episode rate (p < 0.001) The hydroxyurea group - 2.5 per year

The placebo group - 4.5 crises per year

When considering severe pain requiringhospitalization the median annual rate (p < 0.001) hydroxyurea group -1.0 hospitalization per year

placebo group -2.4 hospitalization per year

Acute chest syndrome rate (p < 0.001) hydroxyurea group-16%

placebo group-35%


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Conclusion of the MSH Study

Hydroxyurea therapy can ameliorate theclinical course of sickle cell anemia insome adults with three or more painful

crises per year


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Stroke Prevention Trial (STOP)(N Engl J Med 1998;339:5-11)

HypothesisHypothesis - Prophylactic blood transfusiontherapy in patients with elevated cerebral bloodflow as measured by transcranial doppler will

lower the risk of stroke by 70 percent ascompared with the risk associated with standardcare


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Design of the STOP Study

Randomized trial

Patients with an average mean velocity > 200cm/sec received one of two options:

Standard supportive care Blood transfusion therapy designed to keep the Hb S

concentration below 30%

Primary endpoint Stroke rates in the treated and control groups


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Methods of STOP Trial

Inclusion criteria Hemoglobin SS or S beta thalassemia zero

Ages 2-16 years of age

All enrolled patients had a mean cerebral blood flowof > 200 cm/sec

Stroke was defined as: focal neurological deficitand MRI findings

130 patients were enrolled


13/36Copyright restrictions may apply.

Adams, R. J. Arch Neurol 2007;64:1567-1574.

Kaplan-Meier estimates of the probability of remainingstroke free in children randomized to receive

either regular blood transfusions or standard care


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Conclusions of the STOP Study

Children with hemoglobin SS or SBthalassemia zero between 2 and 16 yearsof age should be screened with TCD

measurement

If the patient meets the high-risk TCDcriterion

regular blood transfusions are recommendedfor an indefinite period of time


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Secondary Analyses

Define Assessment of non-primary outcome measures that

were collected in the course of the trial

MSH- Primary Outcome Measure = Painful episodes STOP- Primary Outcome Measure= Strokes

Difference between primary and secondaryoutcome measures

Sample size is based on primary outcome Less rigorous adjudication process

Intention to treat analysis is often not applied


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Secondary Analyses(continued)

MSH: Secondary outcome measures-listed in theprimary manuscript

Incidence of ACS

blood transfusions therapy hepatic sequestration

death

STOP

None listed in primary manuscript

Level of significance for secondary analyses MSH- 0.01

STOP- none listed


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Secondary Analysis of MSH Trial(Effect of Hydroxyurea on Mortality and Morbidity inAdult Sickle Cell Anemia-JAMA. 2003;289:1645-1651 )

Objective

To determine whether hydroxyurea attenuates mortality inpatients with SCA

Design Nine year observational follow-up study of mortality in

patients MSH follow-up

Results

Taking hydroxyurea was associated with a 40% reductionin mortality (P= .04)

Conclusions

Adult patients taking hydroxyurea have reduced mortality


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Bias in Observational Studies Volunteer bias

Individuals who volunteer for studies are healthier thanpeople who do not Healthy user bias

Individuals who engage in activities that are good forthem are fundamentally different from those who dont

Adherence bias Individuals that adhere to a therapy are quite different

than those that do not Wealthy bias

Individuals who are wealthy, and able to participate inclinical trials are different than those who are not

Hematologist bias Hematologist may be more likely to encourage and

continue hydroxyurea among individuals with lower co-

morbidities i.e. no renal disease


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The MSH was not designed to detect specifieddifferences in mortality

The strength of statistical evidence forsecondary analysis was pre-determined at amore stringent level than the primary end pointtrial design of alpha = .05

The nominal Pvalues should be regarded asindicators of association, not tests ofa priorihypotheses, and should be interpretedcautiously

METHODS Section (taken from manuscript)


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Implications

Many Sickle Cell Disease programs have

elected to use hydroxyurea among adults withsickle cell disease based on these data

Opportunity for a formal trial testing thebenefit of hydroxyurea on survival is less likely

to occur lack of equipoise among hematologists


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0.01Fetal hemoglobin insickle cell anemia:

determinants of

response to hydroxyurea

Steinberg, et al.(1997)

0.05Cost-effectiveness of

hydroxyurea in sickle cellanemia

Moore, et al.

(2000)

0.05Effect of hydroxyurea onmortality and morbidity inadult sickle cell anemia:risks and benefits up to 9

years of treatment

Steinberg, et al(2003)

0.01Hydroxyurea and sicklecell anemia: effect on

quality of life

Ballas, et al.(2006)

Level ofsignificance

Title

MSH

Secondary analysis


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Implications of the MSH trialfor Pediatrics

Blood. 1999 Sep 1;94(5):1550-4

One short term single arm safety trial wascompleted among children Age 5 to 15 years with hemoglobin SS

no child with a diagnosis of hemoglobin SC

Follow up 68 children reached maximum tolerated dose (MTD)

52 were treated at MTD for 1 year

No significant toxicity

Efficacy was not assessed


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Drift in Clinical Practice afterCompletion of Landmark Trials

Defined Physician practice that is based on the results

from a landmark clinical trials to in groups ofpatients that were not included in the trial


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Drift in clinical practice based onresults of MSH Trial

Physicians have elected to treat children withhydroxyurea after multiple episodes of ACS

Two major assumptions ACS is similar in adults and children

Risk and Benefit ratio for adults is the sameas for children

A h i A i d i h ACS i


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0

20

40

60

80

100

0-2 2-4 4-6 6-8 8-10 10-12 12-20

Age (yrs)

ACS

rate(/1

00p

t-yrs)

AsthmaticNot Asthmatic

Blood 2006;108(9):2923-7

Asthma is Associated with ACS in

Children with Sickle Cell Anemia


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Increased Presenting Temperature (> 390C) in ACS by Age

0

10

20

3040

50

60

70


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Presenting Symptoms of Patients with ACS by Age

0

10

20

3040

50

60

70

8090

100

Fever Cough Chest Pain Shortness of

Breath

Severe Chest

Pain

Symptom

PercentPresenting

Ages 2-4

Above Age 20

Blood. 1997 Mar 1;89(5):1787-92.


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ACS In ChildrenDifferent than Adults

Asthma is a risk factor for ACS amongchildren

ACS occurs more often in children thanadults

ACS presents differently in children thanadults


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Not statedCan peak systolic velocities be used for prediction of stroke in sicklecell anemia?

Jones, et al.(2004)

Not statedStroke and conversion to high risk in children screened withtranscranial doppler ultrasound during the STOP study

Adams, et al.(2004)

0.05Magnetic resonance angiography in children with sickle cell diseaseand abnormal transcranial doppler ultrasonography findings

enrolled in the STOP study

Abboud, et al.(2004)

0.05Effect of long-term transfusion on growth in children with sickle cellanemia: results of the STOP trial

Wang, et al.(2005)

0.05Regular transfusion lowers plasma free hemoglobin in children withsickle cell disease at risk for stroke

Lezcano, et al.(2006)

Not statedSTOP: extended follow-up and final resultsLee, et al.(2006)

0.05Elevated blood flow velocity in the anterior cerebral artery andstroke risk in sickle cell disease: extended analysis from the STOPtrial

Kwiatkowski, et al.(2006)

Level of significanceTitle

Secondary analyses from the STOP Trial


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Risk-Benefit ratio for HU in children

may not be the same as adults

The majority of pediatric drug use is offlabel because most therapeutic agentshave not been labeled by the FDA for use

in children In 1997 Congress approved the Food and

Drug Administration Modernization Act

An attribute of this act is the authorization of6-month marketing protection extensionincentive for the pharmaceutical company


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Peer-Reviewed Publication of Clinical

Trials Completed for Pediatric ExclusivityJAMA. 2006;296:1266-1273

Systematic evaluation of 253 pediatric trials 30% had negative results

changes included no meaningful clinical activity

black box warning increased mortality reported in the product compared to

placebo

In the case of hydroxyurea limited incentive for pharmaceutical companies to

support a trial for pediatric exclusivity Pediatric Academic Community must become

advocates for such trials NIH, ASH, ASPHO


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Implications of the MSH trialfor Pediatrics

One short term single arm safety trial wascompleted among children

Age 5 to 15 years with hemoglobin SS no child with a diagnosis of hemoglobin SC

Follow up 84 children followed 6 months

34 children followed 4 months

Hydroxyurea Usage


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Hydroxyurea Usageamong 24 Pediatric Clinical sites

0-5%

5-10%

>10%, < 20%

> 20%

Highest use-30%Lowest use-3%


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A Simple Approach

Quarterly survey of patients with 3 or moreadmissions for pain (ICD 9 code for pain)

Evaluation for asthma If no asthma begin discussion of HU

If asthma, maximize treatment before use of HU

Re-evaluate understanding of pain action plan

Medical Social Worker assessment

Full disclosure and Parent Handbook- returnback to clinic to start HU

Persistence of missed appointment-removedfrom taking the HU


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Thank You!

london limitation of clinical trials

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