RESEARCH UPDATE 2012 Mara L Becker, MD MSCE, Associate Professor of Pediatrics, UMKC, Children’s Mercy Hospitals and Clinics, Kansas City, MO

1. RESEARCH UPDATE
2012 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

2. Disclosures

3. 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

4. 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

5. 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

6. Children are not little adults!
Lucas at The Magic House– St Louis, MO

7. 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

8. And don’t underestimate the effects of
hormones… yikes!
Courtesy of Greg Kearns, PharmD, PhD

9. Why should children be included in
research?
 If we don’t include children in research, we leave
them vulnerable to:
 Incorrect drug dosing
 Sideeffects
 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

10. 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

11. 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 individual
needs 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

12. 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?

13. 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

14. How will my child be protected?
 http://www.nhlbi.nih.gov/childrenandclinicalstudies
/safety.php

15. 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.

16. 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.

17. 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

18. 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

19. Types of Research
 Observational Studies
 Translational Studies
 Clinical Trials
 Comparative Effectiveness Research (CER)

20. 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

21. 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.

22. 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

23. 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

24. 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 Basic Science/bench experiments
explore medication safety once drug
approved by FDA

25. What do we have going on in clinical
trials in the US?

26. 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%

27. 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

28. Biologics: CIMZIA
ClinicalTrials.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)

29. Biologics: SIMPONI
ClinicalTrials.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.

30. Biologics: Actemra
Clinical 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

31. Biologics: Actemra
Clinical 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

32. Vaccine safety in JIA: Gardasil
Clinical 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.

33. 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

34. 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

35. Behavioral: WebSmart
Clinical 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

36. For those interested in the newest drug
targets…
Photograph: Ruth Orkin/Hulton Archive/Getty Images

37. 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

38. 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

39. 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)

40. Comparative Effectiveness Research
Agency 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??

41. Comparative Effectiveness Research
Wikipedia
 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

42. Comparative Effectiveness Research
why useful for JA?
 Randomized Clinical Trials:  CER:
 Expensive and time  More generalizable: ―real
consuming world‖
 YEARS to complete and  Easier recruitment (less
millions of dollars inclusion/exclusion
 Complex (inclusion/exclusion restrictions)
criteria)  ―head to head‖ comparisons
 Hard to recruit, especially in  Can assess patient-relevant
rare conditions outcomes, and clinically
meaningful outcomes
 Can be less expensive
 Potential to compare
treatments at an individual
and population level

43. 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.

44. Role of the Arthritis Foundation
 Direct research grants  AF support for CARRA
through the foundation to and CARRA sponsored
support research that: research
 biomarkers that predict  http://www.arthritis.org/
disease outcome, measure carra.php
response to treatment in  http://www.arthritis.org/
JA. ja-research.php
 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.

45. Fundraising
 AF- sponsored events  Friends of CARRA
 Jingle bell run/walk  raises money through
 Arthritis walk private donations, grants
and various fundraisers
put on by parents and
 Locally sponsored friends across the country
fundraisers  All of money raised goes
 Can be designated to be directly to CARRA to
used in childhood fund research to find the
arthritis research only cause and cure for
rheumatic diseases in
children.

46. Children in Clinical Studies:
No More Hand Me Downs!
 YouTube video for Families

47. Sir William Osler
―The future is today‖

48. Sites to look through
 http://www.clinicaltrials.gov/ct/info/resources
 www.ChildrenAndClinicalStudies.nhlbi.nih.gov
 https://prcsg.org/
 http://www.carragroup.org/

49. And… we’re done!! Time to take off!