RESEARCH UPDATE2012 JUVENILE ARTHRITIS CONFERENCE, ST LOUIS, MO

Mara L Becker, MD MSCE

Associate Professor of Pediatrics, UMKC

Children’s Mercy Hospitals and Clinics, Kansas City, MO

Disclosures

Break Down

Why do we need to be even talking about research in children?

What makes kids different?

How can research benefit my child?

Research Basics

Research vs. clinical care, risks vs. benefits, safety

Types of research

Examples of new clinical trials currently or soon to be enrolling

Other ways of contributing/getting involved

Sir William Osler, 1903―the most influential physician in history‖

―Who can tell of the uncertainties of medicine as an art? The

science on which it is based is accurate and definite enough…

but no two individuals react alike and behave alike under the

abnormal conditions which we know as disease‖

―The good physician treats the disease; the great physician

treats the patient who has the disease‖

His description of the inadequacy of treatment methods for

most disorders was a major factor leading to the creation of

the Rockefeller Institute for Medical Research in New York

Startling facts…

• By age 5 yrs, 95% of children have been prescribed a medication, with an average of 8.5 prescriptions and 5.5 different medications

• Medicines, devices and treatments are often NOT tested in children

– In fact, 70% of medicines prescribed to children have been tested ONLY IN ADULTS

• ―Off-Label‖ use of drugs in children is commonplace

– 79% of hospitalized children received at least 1 off label drug

– Utilize a weight based dose adjustment for children

– Necessary… but NOT ENOUGH!!Loebstein R et al, Pediatr Rev, 1998 (19)12:423-428, Shah S et al, Arch Pediatr Adolesc Med, 2007 (3) 161: 282-90

Children are not little adults!

Lucas at The Magic House– St Louis, MO

Stages of growth: Makes pediatric

patients unique at every stage

• Differences in digestion and enzyme function

• Differences in muscle mass and organ size

• Differences in the effect of therapies upon a growing body

– Are there long term consequences?

• Differences in how the disease acts in kids compared to adults

http://www.nhlbi.nih.gov/childrenandclinicalstudies/whyclinical.php

And don’t underestimate the effects of

hormones… yikes!

Courtesy of Greg Kearns, PharmD, PhD

Why should children be included in

research?

If we don’t include children in research, we leave them vulnerable to:

Incorrect drug dosing

Side effects

Doesn’t work

Not being prioritized for:

research targeted at disease CURE

genetic risk studies and counseling for future risk

Understanding the role of disease prevention

Understanding how complementary approaches may affect disease

Identification of biomarkers to guide disease activity or inactivity

Examples of HOW research can help

my child?

• Find the best doses of medicines to prevent harmful effects or under treatment

• Making safe and easily administered medicines for kids (chewables, liquids, yummy tasting!)

• Finding treatments to conditions that are expressed differently in kids compared to adults (Juvenile arthritis)

• Finding treatments for new or existing diseases to improve health in the future (vaccines)

• Understand how medicines affect growing children and their development

Research vs. Clinical Care

• Research is done to help find out if a treatment or procedure is good for a large group of people with a certain disease or condition. Research helps to answer questions for the future health of those populations. Standard medical care, however, focuses on individualneeds in the present

• Similarities:

– Researcher and your healthcare provider can be the SAME person

– Setting may be in your regular clinic

– The treatments may seem the same

Research vs. Clinical Care: questions to

ask

• How is this different from standard care?

– Will I see different doctors and nurses for the study?

– Will I go to a different hospital or clinic for the study?

– Will the doctors and nurses ask me a lot more questions

about my child's condition?

– Will there be more paperwork or additional tests when

we are in the study?

– Will there be more rules and deadlines in the study?

Will my child benefit?

Research is done to gain information about a

disease, condition, drug or treatment that will

benefit children in the future– different than regular

medical treatment that is given to help a specific

child

However- there are potential benefits:

Helping future generations

Having access to new drugs or treatments, doctors or

other families with same condition

Getting closer monitoring or additional testing

How will my child be protected?

http://www.nhlbi.nih.gov/childrenandclinicalstudies

/safety.php

How will my child be protected?

Research team

Investigator, doctors, nurses, statistical experts, pharmacists

Determine the right study, performed in the right number of

patients, done in the right way, with the right participants

Institutional Review Board

an independent committee that reviews research plans and

consent forms to make sure that people in a study are

informed and protected. They review studies both before

they start and throughout the study.

Protection of study participants, cont.

Informed consent/Patient assent

Parent is given details about a study so that you can decide if your child should join a study. You are "informed" so that you can give your "consent" or okay. Nothing can happen until you consent to it.

Most children from age 7 can understand basic information if it is given at their level. So, in most studies, children are now asked if they agree (assent) to be in a study and are asked to sign an assent form.

Data and safety monitoring board/medical monitor

impartial Board/person that oversees studies and says if a study should be changed or closed at any time for safety issues.

And remember your rights…

Ask as many questions as you’d like

You can say NO at any time, for any reason

www.rfried.info

Research Organizations Specific to

Pediatric Rheumatology

CARRA: Childhood Arthritis and Rheumatology

Research Alliance

Typically manages investigator-initiated studies

PRCSG: The Pediatric Rheumatology Collaborative

Study Group

Handles drug industry-initiated research

Types of Research

Observational Studies

Translational Studies

Clinical Trials

Comparative Effectiveness Research (CER)

Observational studies

Retrospective

In the past

Likely no consent will be obtained

Combine clinical data (without identifiers) to look for associations

This is a big part of the research we have to go on from the past

Ex:

Arthritis Rheum. 1977 Mar;20(2 Suppl):327-31.

Drs. Sullivan, Cassidy and Petty evaluated the charts of 33 patients with JDM treated with steroids, and found that the outcomes of these children were infinitely better than children NOT treated with steroids

Observational Studies

Prospective:

Current/future

Collect specific information on patients, often over time

Registry

Ex.

CARRAnet registry (CARRA= Childhood Arthritis & Rheumatology Research Alliance) observational retrospective and prospective study that enrolls children

and adolescents with major rheumatic diseases followed at participating study sites. All patients with defined rheumatic diseases who are 21 years of age or younger and who are seen/followed at a CARRA site for medical care will be approached for participation in the registry.

Translational Studies

Used as a bridge linking bench/basic scientific research with the patient

Multiple disciplines often involved

Goal for faster application of knowledge to patient

Usually a combined collection of clinical information and biologic sample(s) (blood, urine, tissue, hair, etc)

Ex.

Arthritis Rheum.2010 Jun;62(6):1803-12.

My work is in measuring methotrexate metabolites in cells to determine if different patterns or genetic associations are predictive of better or worse response to the medicine

Clinical Trials

Compares 1 or more treatments

Often randomized

Means your child may NOT get active drug/therapy

Treatment follows very exact guidelines

protocol

Not all patients will qualify

Inclusion and exclusion criteria

Most scientifically rigorous and most expensive

Clinical Trials

Phase 1

Safety doses

Phase 2

Efficacy doses

Phase 3

Compare drug to placebo, or current treatment- does it work? Is it safe?

Phase 3 OLE

Open label extension gathers additional safety data and longer term info about treatment effects

Phase 4

Large observational registries to explore medication safety once drug approved by FDA

Basic Science/bench experiments

What do we have going on in clinical

trials in the US?

TRial of Early Aggressive Therapy in

Polyarticular Juvenile Idiopathic Arthritis

2 arms

Methotrexate subcutaneously OR

Methotrexate subcutaneous, enbrel, steroids

Both arms had patients who achieved clinically inactive disease at 6 months

Methotrexate only: 23%

Triples (M+E+S): 40%

Both arms (although fewer) had patients who reached clinical remission on medication

Methotrexate only: 7%

Triples (M+E+S): 21%

RAPPORT: IL-1 TRAP in systemic JIA

Closed to enrollment

Last patient will finish in December 2012

3 translational studies are attached to this trial

Analysis will begin in January 2013

Biologics: CIMZIAClinicalTrials.gov Identifier: NCT01550003

Pediatric Arthritis Study of Certolizumab Pegol (PASCAL): Phase 3 with OLE- all patients receive drug

Anti-TNF-α monoclonal antibody—fragmented

Given subcutaneously every 2 weeks

Inclusion Criteria: Diagnosis of Polyarticular-course Juvenile Idiopathic Arthritis (JIA) for at least

6 months prior to Baseline

Children and adolescents, aged 2 to 17 years (inclusive); weight ≥ 10 kg

Inadequate response or intolerance to at least 1 Disease-Modifying Antirheumatic Drug (DMARD) (previous exposure to a maximum of 2 biologic agents will be allowed)

Methotrexate (MTX) and oral Corticosteroids will be allowed at stable doses prior to Screening

Inadequate response or intolerance to Methotrexate (MTX)

Biologics: SIMPONIClinicalTrials.gov Identifier: NCT01230827

Safety and Efficacy of Golimumab in Children With JIA and Multiple Joint Involvement Who Have Poor Response to Methotrexate (GO KIDS) Phase 3 (randomized placebo arm after 16 weeks on therapy through

48 weeks)

Anti-TNF-α monoclonal antibody--Given once a month injection

Inclusion Criteria: Diagnosis must have been before the patient's 16th birthday

Disease duration of at least 6 months before study entry

Must have >=5 joints with active arthritis

Must be taking a stable dose of methotrexate

May take a stable dose of prednisone less than 10 mg/day 4 weeks prior to entry or may take a stable dose of NSAIDS (non-steroidal anti-inflammatory drugs) 2 weeks prior to entry

Must have qualifying laboratory values at the first visit.

Biologics: ActemraClinical Trials.gov Identifier NCT01603355

Tocilizumab (anti IL-6 receptor antagonist) in the Management of Juvenile Idiopathic Arthritis Associated Uveitis Phase 1 and Phase 2, pharmacokinetics study (will measure blood

levels of Tocilizumab, and assess safety )

Tocilizumab given IV every 4 weeks (dose depending on weight)

JIA- associated Uveitis (ages 2-17 yrs)

Oregon Health and Science University (not yet recruiting)

Inclusion Criteria:

Subjects with Juvenile Idiopathic Arthritis

Subjects with vision-threatening autoimmune uveitis.

Failure to respond to methotrexate or at least one other systemic immunosuppressive or intolerance to such medications due to side effects.

bilateral eye disease.

If subjects are on oral corticosteroids, the dosage must be stable for 2 weeks prior to baseline and not exceed 10 mg per day or 2mg/kg/day (whichever is less) of prednisone

Must have a chest radiograph within 3 months prior to enrollment

Biologics: ActemraClinical Trials.gov Identifier NCT01455701

A Study of Tocilizumab in Patients Less Than 2 Years Old With Active Systemic Juvenile Idiopathic Arthritis Phase 1 and Phase 2, pharmacokinetics study (will measure blood

levels of Tocilizumab, and assess safety in this age group)

Tocilizumab (Anti IL-6 Rab, IV every 2 weeks x 12 weeks)

Inclusion Criteria: Patients, less than 24 months old at baseline

Diagnosis of systemic juvenile idiopathic arthritis (sJIA)

Duration of systemic juvenile idiopathic arthritis (sJIA) lasting at least 3 months since the onset of sJIA symptoms

Presence of active disease

Uncontrolled disease despite treatment with non-steroidal anti-inflammatory drugs and corticosteroids

Vaccine safety in JIA: GardasilClinical Trials.gov Identifier NCT00573651

Safety and Efficacy of Gardasil in Females With Juvenile Idiopathic Arthritis (JIA)/Seronegative Arthritis (CHASE) Phase 4 safety observational study after vaccine administered at 0, 2

and 6 months

Inclusion Criteria: Female patients, age 9-26 years, with polyarticular JIA, pauciarticular

JIA, and sero-negative arthritis.

Biologics: General- when to stop?Clinical Trials.gov Identifier NCT00792233

Determining Predictors of Safe Discontinuation of Anti-TNF Treatment in JIA Ages 4-20 years

Phase 4 study (but also a translational component)

Looking for predictors of safe discontinuation of anti-TNF therapy

Inclusion Criteria:

Diagnosis of polyarticular JIA or extended oligo JIA

Receiving therapy with one of the currently available anti-TNF biologic

Receiving slit lamp exams performed at regular intervals

Absence active arthritis/active disease (several criteria included)

Exclusion Criteria:

Diagnosis of a type of JIA other than polyarticular JIA

Diagnosis of another inflammatory disease that may affect laboratory results or ability to discontinue anti-TNF biologic therapy

previous treatment with rituximab

concurrent treatment for JIA with corticosteroids >0.2 mg/kg/day OR >10 mg/day

Behavioral: Jointstrong

Clinical Trials.gov Identifier NCT01166750

Jointstrong Intervention for Juvenile Arthritis Computer based intervention for 8 weeks

CD-ROM intervention (randomized) for behavioral modification techniques for controlling symptoms of arthritis. Weekly modules with ―homework‖, daily questionnaire for patient for 2 week time period

University of Kansas Medical Center

Inclusion Criteria 8-12 years of age

diagnosis of JA by a pediatric rheumatologist using established criteria

have JA-related (joint) pain occurring on an average of at least once per week

Behavioral: WebSmartClinical Trials.gov Identifier NCT01541917

Efficacy of Web-based Pain Self-management for Adolescents With Juvenile Idiopathic Arthritis (WebSMART) test of online coping skills training program for English- and Spanish-speaking

adolescents with JIA

experimental group :12-week interactive online multi-component treatment protocol including targeted disease education, training in empirically supported cognitive-behavioral coping skills, and social support augmented by monthly telephone contact with a nurse

control group:12 weeks of guided access to extant online resources for disease education and additional attention to own best efforts at managing JIA via monthly telephone contact with a nurse.

Inclusion Criteria: 12-18 years of age (inclusive)

diagnosed with JIA by a pediatric rheumatologist

able to speak and read English and/or Spanish

able to complete online measures

reporting pain in at least one joint over the past 6 months

For those interested in the newest drug

targets…

Photograph: Ruth Orkin/Hulton Archive/Getty Images

Kinase Inhibitors: Block cytokine effects Jak 3(CP-690,550; Tofacitinib)

Pharmacokinetics Of CP-690,550 In Pediatric

Patients With Juvenile Idiopathic Arthritis (JIA)

ClinicalTrials.gov Identifier: NCT01513902

Long-Term Safety Study Of CP-690,550 In Patients

With Juvenile Idiopathic Arthritis

ClinicalTrials.gov Identifier: NCT01500551

Pfizer: Czech Republic

Kinase Inhibitors: Block cytokine effects Syk Kinase Inhibition (R935788)

Nothing I could find in JIA

Three completed Phase 2 studies in RA

ClinicalTrials.gov Identifier: NCT00326339

ClinicalTrials.gov Identifier: NCT00665925

ClinicalTrials.gov Identifier: NCT00326339

New Cytokine Targets

Anti IL-17: monoclonal antibody

Phase 2: Psoriasis, Crohn’s disease, RA

Anti IL-12/IL-23: monoclonal antibody: Ustekinumab

Phase 2: Psoriatic arthritis

Phase 3: Psoriatic arthritis (ongoing in adults)

Comparative Effectiveness ResearchAgency for Healthcare Research and Quality definition

“A type of health care research that compares the

results of one approach for managing a disease to the

results of other approaches. Comparative effectiveness

usually compares two or more types of treatment, such

as different drugs, for the same disease. Comparative

effectiveness also can compare types of surgery or

other kinds of medical procedures and tests. The results

often are summarized in a systematic review.”

What does this actually mean??

Comparative Effectiveness ResearchWikipedia

Comparative effectiveness research (CER) is the direct comparison of existing health care interventions to determine which work best for which patients and which pose the greatest benefits and harms. The core question of comparative effectiveness research is which treatment works best, for whom, and under what circumstances

These clinical research trials measure effectiveness—the benefit the treatment produces in routine clinical practice.

This is different than many regular clinical trials, which measure efficacy--whether the treatment works or not in a controlled environment such as a clinical trial

Comparative Effectiveness Research

why useful for JA?

Randomized Clinical Trials: Expensive and time

consuming

YEARS to complete and millions of dollars

Complex (inclusion/exclusion criteria)

Hard to recruit, especially in rare conditions

CER: More generalizable: ―real

world‖

Easier recruitment (less inclusion/exclusion restrictions)

―head to head‖ comparisons

Can assess patient-relevant outcomes, and clinically meaningful outcomes

Can be less expensive

Potential to compare treatments at an individual and population level

CER in Juvenile Arthritis: the time is

NOW… or soon!

CARRA Consensus Treatment Plans (CTPs)

Observational CER within the CARRA registry

Formulated for several pediatric rheumatic diseases

CTPs developed over the past 1-2 years by polling the

CARRA community of pediatric rheumatologists and reaching

consensus about the most prevalent/agreed upon treatment

plans for specific diseases

Now, ready to implement and study what plans are best!

Using the CARRAnet registry as the vehicle to collect clinical

information on response/improvement, safety, patient quality

of life, etc.

Role of the Arthritis Foundation

Direct research grants through the foundation to support research that:

biomarkers that predict disease outcome, measure response to treatment in JA.

Develops and/or assesses new drugs and non-pharmacologic methods to improve JA.

Assesses comparative effectiveness of different interventions for JA using the CARRA network.

AF support for CARRA and CARRA sponsored research

http://www.arthritis.org/carra.php

http://www.arthritis.org/ja-research.php

Fundraising

AF- sponsored events

Jingle bell run/walk

Arthritis walk

Locally sponsored fundraisers

Can be designated to be used in childhood arthritis research only

Friends of CARRA

raises money through private donations, grants and various fundraisers put on by parents and friends across the country

All of money raised goes directly to CARRA to fund research to find the cause and cure for rheumatic diseases in children.

Children in Clinical Studies:

No More Hand Me Downs!

YouTube video for Families

Sir William Osler

―The future is today‖

Sites to look through

http://www.clinicaltrials.gov/ct/info/resources

www.ChildrenAndClinicalStudies.nhlbi.nih.gov

https://prcsg.org/

http://www.carragroup.org/

And… we’re done!! Time to take off!