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