development of evidence based “best standard treatments” in pediatric rheumatology carol a....

Development of Evidence Based

“Best Standard Treatments” in Pediatric Rheumatology

Carol A. Wallace MDProfessor of Pediatrics

University of Washington School of MedicineSeattle Children’s Hospital and Research Institute

Immediate Past Chair of CARRA

Why do we want “Best Standard Treatments”?

• Standardized care results in decreased variation in patient care, which has been shown to result in improved quality and outcomes

• Enable comparative effectiveness research to identify the safest, most effective and most cost effective treatments

• Prevent complications by use of safest possible treatments

• Disseminated widely to improve overall standards of patient care nationwide

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Annual USA Cancer Mortality Rate Children <15 Years

CCG

NWTSG

IRSG

CALGB Pediatric Division

SWOG Pediatric DivisionPOG

The National Childhood Cancer Mortality Rate and the Pediatric Cooperative Groups

2000

Mortality per

100,000, Age-

Adjusted

2005

COG

How do we develop evidence based

Best Standard Treatments?• Analyze data from clinical trials• Analyze data from large prospective

cohorts followed from initial presentation with detailed information on treatment and outcomes

We have neither available data sources…

In the absence of data, one approach is to start with development of

“Consensus Treatment Plans”

• Consensus formed; with broad input• Reasonable, common and practical• Once developed, these can facilitate

the development of evidence based Best Standard Care by:– Decreasing treatment variation– Enabling analysis of prospectively collected data

of presenting features, treatments and outcomes

Comparative Effectiveness Research in Pediatric Rheumatic Diseases: Leveraging

CARRA for Improved Child Health

In response to NIAMS RFA 05-AR-102

CARRA-“ ”

Childhood

Arthritis and Rheumatology

Research Alliance

CARRA is:

A research net work of North American Pediatric Rheumatologists and Health Care Professionals dedicated to improving the treatment and health related outcomes of children with rheumatic diseases through clinical research.

CARRA Site Map

CARRA ORGANIZATIONAL STRUCTURE

Elected Steering CommitteeChairs of the Disease Committees

Small and Large Center Reps, Finance Chair, Past Chair

Chair, Vice Chair, JIA Research Committee

SLE Research Committee

JDM Research Committee

Pain Research Committee

Vasculitis/Scleroderma Research Committee

Translational Research and Technology Committee

FinanceCommittee

304 members(71 trainees)

www.carragroup.org

92 SITES

Small Center RepLarge Center Rep

What makes CARRA a Network?

Member Participation

Disease Specific Committee work

Conduct of Research

Education, training and mentoring

Annual Meeting

Collaborations with other organizations

A Research Network Can…

Improve the standard of care through clinical studies

Promote a “culture” of research at Pediatric Rheumatology sites

Develop Best Standard Treatments for better patient outcomes

Specific Aims CARRA-• To develop multiple standardized treatment

plans for use in new onset patients with: JIA, SLE, JDM and localized scleroderma– Use of consensus methodology– Specify of outcome measures, data collection

details and time points• Develop mechanisms to enable rapid

dissemination and use of the consensus developed treatment plans

• Develop analysis plans for the data collected to determine the clinical efficacy and safety of patients treated with these plans

Overall Concept of CARRA-• When a new patient presents, a physician

would choose to use one of the standardized treatment plans that most fits what they would normally do.

• Data would be collected on the patients treated with these standardized treatments

• Data would be analyzed to determine the most efficacious treatment with the least side effects

• Thru this process, we would create evidence based “Best Standard Treatment”

Carol Wallace (contact PI) Norm Ilowite (PI)

JDM Module Ann Reed - Leader

JIA Module Yuki Kimura- Leader

Linear Scl Module Rob Fuhlbrigge-Leader

SLE ModuleEmily Von Scheven Leader

Adam HuberCo-leader

Esi Morgan DeWittCo-leader

Hermine BrunnerCo-leader

Suzanne LiCo-Leader

CARRA-


Dan Solomon

Overall Grant Consultant

JDM Module Ann Reed -Leader

JIA Module Yuki Kimura-Leader

Linear Scl Module Rob Fuhlbrigge-Leader

SLE ModuleEmily Von Scheven Leader

Adam HuberCo-leader



Suzanne LiCo-Leader

Advisory BoardChair- Edward GianniniDan Solomon, Brian Feldman, Pamela Weiss, Peter Boehm, Vincent Del Gaizo

CARRA-


Dan Solomon

Overall Grant Consultant

JDM ModuleAnn Reed - Leader

JIA Module Yuki Kimura-Leader

Linear Scl Module Rob Fuhlbrigge -Leader

SLE Module Emily Von SchevenLeader Lay MembersLay Members

Lay Members Lay Members

Adam HuberCo-leader



Suzanne LiCo-Leader

Advisory BoardChair- Edward GianniniDan Solomon, Brian Feldman, Pamela Weiss, Peter Boehm, Vincent Del Gaizo

CARRA-

Consensus Methodology Choices

• Convene a panel of experts• NIH model:

– Public discussion of questions and evidence before an expert panel, followed by private unstructured deliberations of the panel

• Delphi Questionnaire Technique• Nominal Group Technique• Combination of the Delphi

Questionnaires and Nominal Group Technique

Development process for Consensus Treatment Plans

***** Workgroup*****



Initial CARRA wide surveys

JIA: new onset systemic JIASLE: new onset nephritisJDM: new onset moderate to severe diseaseLocalized scleroderma: new onset


CARRA wide, case-based treatment survey

Consensus Meeting

CARRA wide survey

Refinement, finalization of plans


Review of literature

Treatment of Linear Scleroderma: Survey of Current Practice

Case 1: 4yo F with 2 mo history of linear scleroderma of lower leg. Lesion crosses ankle and initially had erythematous- violaceous border.

Now warm with SQ tissue loss. Labs show ESR

Treatment of Linear Scleroderma: Survey of Current Practice

MTX only

CS + MTX

Case 1: 4yo F with 2 mo history of linear scleroderma of lower leg. Lesion crosses ankle and nitially had erythematous- violaceous border.

Now warm with SQ tissue loss. Labs show ESR

96% use methotrexate (MTX) + corticosteroid (CS)

4% use MTX only

This looks pretty good. But what about treatment specifics?

Li et al. J Rheum 2010;37: 175-81

What type of CS were chosen?

no CS

Oral CS only

IV CS only

IV + Oral CS

30% use oral CS

39% use IV CS

27% use IV + Oral CS

Case 1: 4 yo F with linear scleroderma of leg4% do not use CS

How about specific CS doses and dosing regimens?

CS use in LS: Dosing regimens and duration

Pred 0.75x6 Pred 0.5 x1

Pred 0.5 x2 Pred 0.5 x6

Pred 0.5 xNS Pred 1 x1

Pred 1 x2 Pred 1 x 2.5

Pred 1 x3 Pred 1 x6

Pred 2 x0.5 Pred 2 x1

Pred 2 x2 Pred 2 x3

Pred 2 x6 Pred 2 xNS

IV 1/wk x1 IV 1/wk x2

IV 1/wk xNS IV 1/mo x1

IV 1/mo x6 IV 1/mo x7



IV 3/mo+add IVMP IV 3/mo xNS

IV 3/wk x0.25 IV 3/wk x0.5 +add IVMP

IV 3/wk x3 IV 3/wk x NS

IV 1/mx6 + pred2/kg x 12 IV 1/m x1 + pred1/kg x1

IV 1/wk x1 +pred 0.5 x1 IV 1/wk x3 +pred0.5x3

IV 1/wkx1 +pred 1/kgx1 IV 1/wk xNS +pred 1/kg x3

IV 1/wkx1 +pred 2/kg x1 IV 1/wkx1 +pred 0.5x1

IV 1/wkx2 +Pred 2/kgQOD x1 IV 1/wk x2 +pred 2/kg x1

IV 3/mo x1 then pred IV 3/mox1 +pred2/kg QOD x1

IV 3/mox3 then pred IV 3/mox1+pred 1/kgx1

IV 3/mo x3 +pred 1/kgx1 IV 3/mox6 +pred 1/kgx1

IV 3/wkX0.25 then pred IV 3/wkX0.25 +pred0.5/kg x2

IV 3/wk x0.25 +pred 0.5x1 IV 3/wk X0.25 +pred2/kg x2

IV 3/wk X0.25 +pred 1/kg x3 IV 3/wk xNS =Pred 1/kg x1

IV 3/wk x0.5 +pred 1/kg x3 IV 3/wk x0.25 +pred 2/kg x1

IV 3/wk x0.5 +pred 2/kg x1 IV 3/wk x0.5 +pred 2/kg x3

IV 3/wk x1 +pred 2/kg x1 IV 3/wk x0.25 +pred 1/kgx 1

IV 3d/mo x 3 mo: 27 PR

Pred 1mg/kg/d x 1 mo: 9 PR

3 main oral CS regimens:-1 mg/kg/d (28)-2 mg/kg/d (18)-0.5 mg/kg/d (11)

4 IV CS regimens:-3d/mo (33)-1/wk (19)-3d/wk (19)-1/mo (5)

MTX Treatment Regimens in LS0.3 pox15 0.3 po x240.3, 0.6 sq/po x 25 0.5 sq x60.5 sq x7 0.5 sq x 90.5 sq x12 0.5, 1 po x 130.5 sq x 13 0.5, 0.75 sq x 130.5,1 sq x14 0.5 sq x180.5, 0.3 sq x21 0.5 po x240.5 sq x24 0.5, 1 sq x260.5 sq/po x36 0.5 sq x12+0.5 NS xNS 0.6 po x120.6sq x15 0.6 sq xNS0.6 sq/po, po x NS 0.75 po x120.75, 1 sq, 0.5po x 24 0.75 po x240.75 sq x 24 0.75 sq x300.75 po x NS 0.8 sq x NS0.875 sq/po, 0.75 sq, 1 po x 14 0.875 sq/po x 241 sq x 3 1 sq x121 sq, 20 sq x13 1 sq/po, 1 sq x151 sq x 15 1 sq, 0.5 sq x 181 sq/po, 15 sq/10po x 18 1 sq x 181 po x 24 1 sq x 241 sq, 0.3po x 24 1 po x 271 sq x 27 1 sq, 0.75sq x301 sq/po x 30 1 sq x301 sq x 36 1 sq x 421 sq x 48 1 sq/po x 481 po, 1 taper x 18 1 sq/10 sq x24+1 sq/po, taper x>12 1 sq, taper x>101 sq x>12 1 sq, 0.5 sq x 12+1 sq x 36+ 1 sq x NS1 sq, 15 po x 24_ 10 sq x1310 po x 15 10 sq/po, 15 po x 2610 sq/po, 15 sq/po x30 10 po x NS12 sq/po x 24 12 po x NS12.5 sq/po,1sq,, 10 po x12 15 po x 1215 sq x12 15 sq/po x 1215 sq x15 15 po x 2415 sq x 24 15 po, 10 po x 2615 sq/po x30 15 sq x 3615 sq/po x 42 15 sq x 48

13 different initial doses27 different initial doses and routes


Case-based survey CARRA wide survey

Consensus Meetings at CARRA

Annual meeting 2010

CARRA wide survey

Refinement, finalization of plans



Consensus methodologies facilitated and promoted the highest quality team work

However, this is REALLY hard and time consuming!

CARRA-

CARRA- Guiding Principles

• Evidence-based when possible– Considered the best available literature

• Compatible with the current practice– Assessed by the surveys

• Consensus agreement– Delphi Questionnaires– Nominal group technique

Development of ConsensusStandardized Treatments

• Distill what we do- using collective judgment and consensus processes

• Forced us to:– Think critically about what we do– Use facts when present, not beliefs

or “this is how I always do this”– Emphasis on decreased variation

Development of Consensus Standardized Treatments

• Not rigorous protocols- but rather menus of standardized treatments

• Not perfect or exactly what each physician might do, but what he/she can live with

• The goal is to reduce variation so we can treat in a standardized fashion, collect data and compare patient outcomes

Common Module Work • Define the patient characteristics

and exclusions for use of the treatment plans

• What to do if better, worse or adverse event

• Essential data to be collected• Essential labs to be collected• Key data collection time points

Challenges• Steroids

– How to standardize dosages and routes– Standardization of steroid taper rate

• JIA:– Patient characteristics: how early to allow treatment -

may need to treat before fulfilling ILAR criteria for JIA– Include a new medication not yet approved?

• SLE: Induction and maintenance, or just induction?

• Linear scleroderma:– Lack of outcome measures – Lack of definitions for improvement, worsening

SLE Breakout sessions

Topic Group CoordinationM= moderatorN= note taker

1 Outcome measures/response variables

M: Hermine BrunnerN: Joyce Hsu

2 Cyclophosphamide plan M: Emily von SchevenN: Eyal Muscal

3 Mycophenolate plan M: Anne EberhardN: Marisa Klein-Gitelman

4 Steroid regimens – doses and tapering

M: Lynn PunaroN: Linda Wagner-Weiner

5 QOL/patient perspectives/ AEs

M: Stacey ArdoinN: Nandini Moorthy, Jenny Palter

Regimen AMTX alone

BMTX + Intravenous steroid

CMTX + Oral prednisone

MTX weekly dose

1mg/kg SQ (max 25 mg)

1mg/kg SQ (max 25 mg) 1mg/kg SQ (max 25 mg)

Steroiddose, Duration

None 30 mg/kg/dose (max 1gm)EITHER: 3 consecutive daily doses/mo, OR: 1 dose/weekDuration: 3 months

2 mg/kg/d (max 60 mg) divided bidDuration: at least 2 weeks

Steroid taper targets

None None Dose reduced to:1 mg/kg/d (max 30 mg) by end of wk 80.5 mg/kg/d (max 15 mg) by end of wk 160.25 mg/kg/d (max 7.5 mg) by end of wk 24Off CS by end of week 48

Localized Scleroderma Consensus Treatment Plans

JIA Module• Developed 4 treatment plans:

– Steroid only– Methotrexate– Anakinra– Tocilizumab

• Possible steroid plans :– IV 30/kg/day X 3 days– Oral

• 1 mg/kg/day – taper over 1, 3 or 6 months• 2 mg/kg/day – taper over 1, 3 or 6 months

ASSESS AT 3 MONTHS If Improved

*If on PO PDN, taper PDN Continue same dose MTX, reassess monthly

If Unchanged , Worse, or on >50% steroid doseContinue same dose PDN and MTX , Plus

Add additional therapy, choose and follow either: anakinra plan or tocilizumab plan

ASSESS AT 1 MONTH

If ImprovedContinue same dose MTXStart/Continue PDN taper,

reassess monthly

If UnchangedIncrease MTX to 1mg/kg (30mg

max) SQ weekly ; Continue same dose PDN , reassess monthly

If WorseIncrease MTX to 1mg/kg SQ

weekly; Increase (or continue) PDN to 2mg/kg (max 100mg);

repeat IV MP, reassess monthlyASSESS AT 1-2 WEEKS

ImprovedTaper PDN (if on)

(choose rapid, fast, slow)

UnchangedContinue same dose PDN

Optional: Add or repeat IV MP (can be weekly)

WorsenedIf not on oral PDN, add at 1mg/kg;

If on PDN, increase to 2mg/kg; Add/Repeat IV MP (can be weekly)

Plan B: MethotrexateMethotrexate (MTX) 0.5mg/kg PO or SQ weekly

Optional corticosteroids : PDN 1mg/kg (60mg max); IV MP pulse 30mg/kg X 3 d

Systemic JIA data collectionCategory Items

History demographics, date symptom onset, comorbidities, medications, recent rash or serositis, suspected MAS

Patient and Physician assessments

painHRQOL physical functionparent/patient global assessmentprovider global assessment

Physical Exam Ht, Wt, BMI, active joint count, hepatomegaly, lymphadenopathy, rash, serositis, splenomegaly

Labs CBC c-reactive protein, ESR, ferritinalbumin, LDH

Treatment-related factors

MedicationsSAE or IME if discontinuation then provide reason


Case-based CARRA wide survey

Consensus Meeting

CARRA wide survey

Refinement, finalization of plans; CARRA 2011 meeting



Consensus Treatment Plans developed for new onset:

• Systemic JIA– Steroids– MTX +/- steroids– Anakinra +/steroids– Tocilizumab +/steroids

• Juvenile Dermatomyositis– Pred + MTX – Pred + MTX + IV methylpred– Pred + MTX + IV methylpred

+ IVIG

• Renal disease in SLE– Cell cept induction– IV cytoxan induction

• Linear Scleroderma– MTX– MTX +Oral steroid– MTX + IV methyl pred

•All Modules have submitted the Treatment Plans and their

development for publication

Next Steps• Parallel to this effort has been the development of

a large foundational pediatric rheumatology registry: CARRAnet – 60 participating pediatric rheumatology sites– 6,000 patients enrolled

• Plan is that new onset patients treated with one of the Consensus Treatment Plans will have specific data collected using the CARRAnet platform

Consensus Treatment Plans

CARRA website

Publication progress: JDM – AC&R SLE – AC&R Systemic JIA – revision AC&R Localized scleroderma – revision AC&R

Implementation of Consensus Treatment Plans

Protocol for the CARRA Registry and Consent form allows for data collection that will cover the basic registry and additional sub-studies.

Actual additional data collection will occur at sites participating in the pilot studies.

All CARRA members are encouraged to use the CTP on new patients, regardless of participation in the pilot studies

Consensus Treatment Plans: Pilot Studies

JDM: Friends of CARRA and CUREJM 10 sites/ 40 patients

Systemic JIA: Arthritis Foundation 15 sites/ 30 patients

SLE: Lupus Foundation of America 15 sites/ 40 patients

Localized Scleroderma: Arthritis Foundation 11 sites/ 50 patients

Future Steps• Analysis of the data collected through the

CARRAnet platform will allow for comparisons between treatments for determination of effectiveness, outcomes and side effects

• Evidence based Best Standard Treatments can then be identified and widely disseminated

• Over time these can be improved upon in an iterative fashion to improve the outcomes of children with rheumatic diseases

• Development of standardized treatment plans for additional phases/categories of disease are underway

ASSESS AT 3 MONTHS Patient on <50% starting steroid dose

Continue to taper PDN, reassess monthlyIf improved, continue PDN taper

If unchanged or worsened, add additional therapy (plan B, C, D)

Patient on >50% starting steroid doseContinue same dose PDN , Plus

Add additional therapy, choose and follow either : methotrexate, anakinra, tocilizumab plan

ASSESS AT 1 MONTH

If ImprovedContinue (or initiate) PDN taper

If Unchanged or WorseIncrease (or continue) PDN to 2mg/kg (max 100mg);

repeat IV MP (can be weekly), reassess monthlyASSESS AT 1-2 WEEKS

ImprovedTaper PDN


UnchangedContinue same dose PDN

Add or repeat IV MP

WorsenedIncrease PDN to 2mg/kg (max

100mg); Repeat IV MP

Plan A: SteroidPrednisone (PDN) 1mg/kg (max 60mg) daily

Optional IV MP pulse 30mg/kg (max 1g) daily for 3 days


*If on PO PDN, taper PDN Continue same dose ANK

reassess monthly

If Unchanged , Worse, or on >50% steroid dose Continue same dose PDN

Plus eitheradd MTX, or switch to tocilizumab plan

ASSESS AT 1 MONTH

If ImprovedContinue same dose ANKStart/Continue PDN taper,

reassess monthly

If UnchangedIncrease ANK to 4mg/kg (200mg max) SQ daily; Continue same dose PDN reassess monthly

If WorseContinue same dose ANK

If not on oral PDN, add or increase PDN to 2mg/kg; Add/Repeat

IVMP; reassess monthlyASSESS AT 1 -2 WEEKS

ImprovedContinue same dose ANK

If on PDN, taper (choose rapid, fast, slow)

UnchangedContinue same dose ANK

If on PDN, continue same dose Optional: Add or repeat IV MP

WorsenedIncrease ANK to 4mg/kg

(200mgmax) SQ daily; If on PDN, continue same

doseOptional: Add or repeat IV MP

Plan C: AnakinraAnakinra (ANK) 2mg/kg (max 100mg) SQ daily

Optional corticosteroids : PDN 1mg/kg (60mg max) with IV MP pulse 30mg/kg/d X 3


*If on PO PDN, taper PDN Continue same dose TOC

reassess monthly

If Unchanged , Worse, or on >50% steroid dose Continue same dose PDN /IV MP pulses

Plus eitheradd MTX or switch to anakinra plan

ASSESS AT 1 MONTH

If ImprovedContinue same dose TOC

Start/Continue PDN taper, reassess monthly

If Unchanged or Worse Continue same dose TOC; If not on oral PDN, add; If

on PDN increase (or continue) to 2mg/kg (max 100mg); repeat IV MP , reassess monthly

ASSESS AT 2 WEEKS

ImprovedIf on PDN, taper


UnchangedIf on PDN, continue same doseOptional: Add/Repeat IV MP

WorsenedIf not on oral PDN, add at 1mg/kg

If on PDN, increase to 2mg/kg; Optional: Add/Repeat IV MP

Plan D: TocilizumabTocilizumab (TOC) 8mg/kg (if >30 kg) or 12 mg/kg (if <30 kg) IV every two weeks

Optional corticosteroids: PDN 1mg/kg (60mg max) with IV MP pulse 30mg/kg/d X 3

development of evidence based “best standard treatments” in pediatric rheumatology carol a....

Documents

standardized care results

research instituteimmediate

pediatric rheumatology

protocolized treatment

decreased variation

improved quality

chair of carra