Pharmacovigilance in Juvenile Idiopathic Arthritis Patients Treated With Biologic Agents and/or Methotrexate

NCT01399281 | Unknown DMC

• 1 other identifier: EU 260353
• Study Type: observational
• Target: 9,000
• Locations: 1 country
• Sites: 1

Brief Summary

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common chronic paediatric rheumatic disease (PRD) and an important cause of short and long-term disability. Although none of the available drugs for JIA has a curative potential, prognosis has greatly improved as a result of substantial progress in disease management. The therapeutic treatment of children with JIA encompasses the use of NSAIDs and intra-articular steroid injections. In those patients not responding to NSAIDs, methotrexate (MTX) has become the disease modifying anti-rheumatic drug (DMARD) of first choice worldwide. For children not responding to MTX, biologic agents recently have become treatment options. PATIENTS AND METHODS: 3-10 year observation study related to children with JIA undergoing treatment with MTX or biologic agents with the following objectives:

1. 1.To create a long-term observational registry of a large population of prevalent and incident cases.
2. 2.Use the accumulating data in the registry to conduct (i) a pharmacovigilance/safety study (primary endpoint) and (ii) estimate effectiveness (frequency and magnitude of response, disease activity over time inhibition or slowing of joint erosions and other radiological evidence of disease progression,), and (iii) estimate adherence to the various treatment regimens. Data from the registry will be used to compare safety and effectiveness profiles amongst the patient cohorts.
3. 3.To identify clinical and laboratory predictors of safety, response to therapy, including remission This project has retrospective (first 3 years) and prospective components (up to 10 years) and will be conducted by the participating centres of the more than 50 countries belonging to the Paediatric Rheumatology INternational Trials Organisation (PRINTO certified ISO 9001-2008, www.printo.it), or the Pediatric Rheumatology European Society (PRES at www.pres.org.uk). The main role of these organisations is to provide a scientific basis for current treatments of paediatric rheumatic diseases.
4. 4.Biologic agents ± MTX agents are able to maintain an acceptable safety profile in the long term in children with different JIA categories while achieving clinical remission and prevent/stop joint erosion development over time. The overall aims are to establish the long term safety of biologic agents and MTX, and their relative effectiveness in children with JIA who need treatment with second line agents.

Conditions

Juvenile Idiopathic Arthritis

Keywords

juvenile idiopathic arthritis, biologics, methotrexate

Outcome Measures

Primary Outcomes (2)

• Safety in patients with JIA on biologics/MTX from 3 to 10 years from drug initiation

  To compare the long term incidence rates of emergent moderate, severe adverse events (AEs) and serious A (SAE) observed in paediatric subjects with JIA. This will include but not be limited to, malignancies, opportunistic infections, autoimmune events, cardiovascular events, central nervous system involvement (e.g. optic neuritis, demyelinating disease), infertility, gastrointestinal bleeding, macrophage activation syndrome (MAS).

  3-10 years

• Long-term efficacy in patients with JIA on biologics/MTX from 3 to 10 years from drug initiation

  To assess the long-term efficacy (magnitude of response, prevention or slowing of joint erosion and damage, and treatment adherence) of biologic agents and MTX for the treatment of children and adolescents with different categories of JIA.

  3-10 years

Secondary Outcomes (6)

• Predictors of safety from 3 to 10 years from drug initiation

  3-10 years

• Risk factor from 3 to 10 years from drug initiation

  3-10 years

• Number of children in treatment with biologics from 3 to 10 years from drug initiation

  3-10 years

• Wrist joint erosion from 3 to 10 years from drug initiation

  3-10 years

• Assess the reasons for stopping drug treatment from 3 to 10 years from drug initiation

  3-10 years

Study Arms (3)

Biologics alone or methotrexate alone

This group mainly refer to children with polyarticular course JIA treated with methotrexate ± biologics,

Biologics and MTX

JIA treated with a combination of biologic and MTX (including any other add on therapy e.g. cyclosporine, leflunomide etc). This group mainly refer to children with polyarticular course JIA treated with MTX ± biologics

NSAIDs and/or steroid injections alone

This group refers to children with mostly oligoarticular persistent course who are usually NOT treated with second line agents and have a more benign course.

Eligibility Criteria

• Age: 6 Months - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Probability Sample

Study Population

Male and female JIA patients selected among the PRINTO centres as part of the routine standard of care

You may qualify if:

• Signed written informed consent by subjects and /or parent or legally acceptable representative;
• JIA (any ILAR category);
• Subjects receiving biologic agents ± MTX, MTX alone, or NSAIDs and/or steroid injections only as per physician discretion.

You may not qualify if:

• Contraindications to biologic agents and/or MTX treatment

Sponsors & Collaborators

• Istituto Giannina Gaslini: lead
• Members of the PRINTO network (PRINTO at www.printo.it): collaborator

Study Sites (1)

IRCCS G. Gaslini

Genoa, 16147, Italy

RECRUITING

Related Publications (26)

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• Ruperto N, Murray KJ, Gerloni V, Wulffraat N, de Oliveira SK, Falcini F, Dolezalova P, Alessio M, Burgos-Vargas R, Corona F, Vesely R, Foster H, Davidson J, Zulian F, Asplin L, Baildam E, Consuegra JG, Ozdogan H, Saurenmann R, Joos R, Pistorio A, Woo P, Martini A; Pediatric Rheumatology International Trials Organization. A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate. Arthritis Rheum. 2004 Jul;50(7):2191-201. doi: 10.1002/art.20288.

  PMID: 15248217 BACKGROUND

• Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, Silverman ED, Nocton JJ, Stein LD, Gedalia A, Ilowite NT, Wallace CA, Whitmore J, Finck BK. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med. 2000 Mar 16;342(11):763-9. doi: 10.1056/NEJM200003163421103.

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• Ruperto N, Lovell DJ, Cuttica R, Wilkinson N, Woo P, Espada G, Wouters C, Silverman ED, Balogh Z, Henrickson M, Apaz MT, Baildam E, Fasth A, Gerloni V, Lahdenne P, Prieur AM, Ravelli A, Saurenmann RK, Gamir ML, Wulffraat N, Marodi L, Petty RE, Joos R, Zulian F, McCurdy D, Myones BL, Nagy K, Reuman P, Szer I, Travers S, Beutler A, Keenan G, Clark J, Visvanathan S, Fasanmade A, Raychaudhuri A, Mendelsohn A, Martini A, Giannini EH; Paediatric Rheumatology International Trials Organisation; Pediatric Rheumatology Collaborative Study Group. A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 2007 Sep;56(9):3096-106. doi: 10.1002/art.22838.

  PMID: 17763439 BACKGROUND

• Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Perez N, Silva CA, Abud-Mendoza C, Burgos-Vargas R, Gerloni V, Melo-Gomes JA, Saad-Magalhaes C, Sztajnbok F, Goldenstein-Schainberg C, Scheinberg M, Penades IC, Fischbach M, Orozco J, Hashkes PJ, Hom C, Jung L, Lepore L, Oliveira S, Wallace CA, Sigal LH, Block AJ, Covucci A, Martini A, Giannini EH; Paediatric Rheumatology INternational Trials Organization; Pediatric Rheumatology Collaborative Study Group. Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet. 2008 Aug 2;372(9636):383-91. doi: 10.1016/S0140-6736(08)60998-8. Epub 2008 Jul 14.

  PMID: 18632147 BACKGROUND

• Lovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, Nemcova D, Mouy R, Sandborg C, Bohnsack J, Elewaut D, Foeldvari I, Gerloni V, Rovensky J, Minden K, Vehe RK, Weiner LW, Horneff G, Huppertz HI, Olson NY, Medich JR, Carcereri-De-Prati R, McIlraith MJ, Giannini EH, Martini A; Pediatric Rheumatology Collaborative Study Group; Pediatric Rheumatology International Trials Organisation. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008 Aug 21;359(8):810-20. doi: 10.1056/NEJMoa0706290.

  PMID: 18716298 BACKGROUND

• Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Perez N, Silva CA, Abud-Mendoza C, Burgos-Vargas R, Gerloni V, Melo-Gomes JA, Saad-Magalhaes C, Chavez-Corrales J, Huemer C, Kivitz A, Blanco FJ, Foeldvari I, Hofer M, Horneff G, Huppertz HI, Job-Deslandre C, Loy A, Minden K, Punaro M, Nunez AF, Sigal LH, Block AJ, Nys M, Martini A, Giannini EH; Paediatric Rheumatology International Trials Organization and the Pediatric Rheumatology Collaborative Study Group. Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis. Arthritis Rheum. 2010 Jun;62(6):1792-802. doi: 10.1002/art.27431.

  PMID: 20191582 BACKGROUND

• Ruperto N, Lovell DJ, Cuttica R, Woo P, Meiorin S, Wouters C, Silverman ED, Balogh Z, Henrickson M, Davidson J, Foeldvari I, Imundo L, Simonini G, Oppermann J, Xu S, Shen YK, Visvanathan S, Fasanmade A, Mendelsohn A, Martini A, Giannini EH; Paediatric Rheumatology INternational Trials Organization (PRINTO); Pediatric Rheumatology Collaborative Study Group (PRCSG). Long-term efficacy and safety of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis: findings from an open-label treatment extension. Ann Rheum Dis. 2010 Apr;69(4):718-22. doi: 10.1136/ard.2009.100354.

  PMID: 20237125 BACKGROUND

• Woo P, Southwood TR, Prieur AM, Dore CJ, Grainger J, David J, Ryder C, Hasson N, Hall A, Lemelle I. Randomized, placebo-controlled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis. Arthritis Rheum. 2000 Aug;43(8):1849-57. doi: 10.1002/1529-0131(200008)43:83.0.CO;2-F.

  PMID: 10943876 BACKGROUND

• Ruperto N, Ravelli A, Castell E, Gerloni V, Haefner R, Malattia C, Kanakoudi-Tsakalidou F, Nielsen S, Bohnsack J, Gibbas D, Rennebohm R, Voygioyka O, Balogh Z, Lepore L, Macejkova E, Wulffraat N, Oliveira S, Russo R, Buoncompagni A, Hilario MO, Alpigiani MG, Passo M, Lovell DJ, Merino R, Martini A, Giannini EH; Pediatric Rheumatology Collaborative Study Group (PRCSG); Paediatric Rheumatology International Trials Organisation (PRINTO). Cyclosporine A in juvenile idiopathic arthritis. Results of the PRCSG/PRINTO phase IV post marketing surveillance study. Clin Exp Rheumatol. 2006 Sep-Oct;24(5):599-605.

  PMID: 17181934 BACKGROUND

• Silverman E, Mouy R, Spiegel L, Jung LK, Saurenmann RK, Lahdenne P, Horneff G, Calvo I, Szer IS, Simpson K, Stewart JA, Strand V; Leflunomide in Juvenile Rheumatoid Arthritis (JRA) Investigator Group. Leflunomide or methotrexate for juvenile rheumatoid arthritis. N Engl J Med. 2005 Apr 21;352(16):1655-66. doi: 10.1056/NEJMoa041810.

  PMID: 15843668 BACKGROUND

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  PMID: 9588731 BACKGROUND

• Beukelman T, Patkar NM, Saag KG, Tolleson-Rinehart S, Cron RQ, DeWitt EM, Ilowite NT, Kimura Y, Laxer RM, Lovell DJ, Martini A, Rabinovich CE, Ruperto N. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res (Hoboken). 2011 Apr;63(4):465-82. doi: 10.1002/acr.20460.

  PMID: 21452260 BACKGROUND

• Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum. 1997 Jul;40(7):1202-9. doi: 10.1002/1529-0131(199707)40:73.0.CO;2-R.

  PMID: 9214419 BACKGROUND

• Wallace CA, Ruperto N, Giannini E; Childhood Arthritis and Rheumatology Research Alliance; Pediatric Rheumatology International Trials Organization; Pediatric Rheumatology Collaborative Study Group. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol. 2004 Nov;31(11):2290-4.

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• Ruperto N, Martini A. Pediatric rheumatology: JIA, treatment and possible risk of malignancies. Nat Rev Rheumatol. 2011 Jan;7(1):6-7. doi: 10.1038/nrrheum.2010.199. Epub 2010 Dec 7. No abstract available.

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• Diak P, Siegel J, La Grenade L, Choi L, Lemery S, McMahon A. Tumor necrosis factor alpha blockers and malignancy in children: forty-eight cases reported to the Food and Drug Administration. Arthritis Rheum. 2010 Aug;62(8):2517-24. doi: 10.1002/art.27511.

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• Simard JF, Neovius M, Hagelberg S, Askling J. Juvenile idiopathic arthritis and risk of cancer: a nationwide cohort study. Arthritis Rheum. 2010 Dec;62(12):3776-82. doi: 10.1002/art.27741.

  PMID: 20827782 BACKGROUND

• Askling J, Baecklund E, Granath F, Geborek P, Fored M, Backlin C, Bertilsson L, Coster L, Jacobsson LT, Lindblad S, Lysholm J, Rantapaa-Dahlqvist S, Saxne T, van Vollenhoven R, Klareskog L, Feltelius N. Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant lymphomas: relative risks and time trends in the Swedish Biologics Register. Ann Rheum Dis. 2009 May;68(5):648-53. doi: 10.1136/ard.2007.085852. Epub 2008 May 8.

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• Askling J, van Vollenhoven RF, Granath F, Raaschou P, Fored CM, Baecklund E, Dackhammar C, Feltelius N, Coster L, Geborek P, Jacobsson LT, Lindblad S, Rantapaa-Dahlqvist S, Saxne T, Klareskog L. Cancer risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor alpha therapies: does the risk change with the time since start of treatment? Arthritis Rheum. 2009 Nov;60(11):3180-9. doi: 10.1002/art.24941.

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• Giannini EH, Ilowite NT, Lovell DJ, Wallace CA, Rabinovich CE, Reiff A, Higgins G, Gottlieb B, Singer NG, Chon Y, Lin SL, Baumgartner SW; Pediatric Rheumatology Collaborative Study Group. Long-term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis. Arthritis Rheum. 2009 Sep;60(9):2794-804. doi: 10.1002/art.24777.

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• Del Giudice E, de Roock S, Vastert SJ, Wulffraat NM, Swart JF, van Dijkhuizen EHP. Patients' and parents' satisfaction to improve patient care in JIA: factors determining acceptable symptom state measured with JAMAR. Rheumatology (Oxford). 2023 May 2;62(5):1920-1925. doi: 10.1093/rheumatology/keac658.

  PMID: 36515484 DERIVED

• Giancane G, Papa R, Vastert S, Bagnasco F, Swart JF, Quartier P, Anton J, Kamphuis S, Sanner H, Glerup M, De Benedetti F, Tsitsami E, Remesal A, Moreno E, De Inocencio J, Myrup C, Pallotti C, Kone-Paut I, Franck-Larsson K, Malmstrom H, Cederholm S, Pistorio A, Wulffraat N, Ruperto N; Paediatric Rheumatology International Trials Organisation (PRINTO). Anakinra in Patients With Systemic Juvenile Idiopathic Arthritis: Long-term Safety From the Pharmachild Registry. J Rheumatol. 2022 Apr;49(4):398-407. doi: 10.3899/jrheum.210563. Epub 2022 Feb 1.

  PMID: 35105709 DERIVED

• Giancane G, Swart JF, Castagnola E, Groll AH, Horneff G, Huppertz HI, Lovell DJ, Wolfs T, Herlin T, Dolezalova P, Sanner H, Susic G, Sztajnbok F, Maritsi D, Constantin T, Vargova V, Sawhney S, Rygg M, K Oliveira S, Cattalini M, Bovis F, Bagnasco F, Pistorio A, Martini A, Wulffraat N, Ruperto N; Paediatric Rheumatology International Trials Organisation (PRINTO). Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adjudication Committee. Arthritis Res Ther. 2020 Apr 7;22(1):71. doi: 10.1186/s13075-020-02167-2.

  PMID: 32264969 DERIVED

• Swart J, Giancane G, Horneff G, Magnusson B, Hofer M, Alexeeva capital IE, Cyrillic, Panaviene V, Bader-Meunier B, Anton J, Nielsen S, De Benedetti F, Kamphuis S, Stanevica V, Tracahana M, Ailioaie LM, Tsitsami E, Klein A, Minden K, Foeldvari I, Haas JP, Klotsche J, Horne AC, Consolaro A, Bovis F, Bagnasco F, Pistorio A, Martini A, Wulffraat N, Ruperto N; Paediatric Rheumatology International Trials Organisation (PRINTO), BiKeR and the board of the Swedish Registry. Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from Pharmachild and national registries. Arthritis Res Ther. 2018 Dec 27;20(1):285. doi: 10.1186/s13075-018-1780-z.

  PMID: 30587248 DERIVED

Related Links

• Official website of the Paediatric Rheumatology International Trials Organisation (PRINTO)

MeSH Terms

Conditions

Arthritis, Juvenile

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Nicola Ruperto, MD, MPH

  Istituto G. Gaslini/ PRINTO

  PRINCIPAL INVESTIGATOR

• PRINTO Member

  All PRINTO members who will receive ethics committee approval

  STUDY DIRECTOR

Central Study Contacts

Nicola Ruperto, MD, MPH

CONTACT

+39-010-382854; nicolaruperto@gaslini.org

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, MPH

Study Record Dates

• First Submitted: July 19, 2011
• First Posted: July 21, 2011
• Study Start: December 1, 2011
• Primary Completion: December 1, 2021
• Study Completion: December 1, 2021
• Last Updated: March 5, 2018

Record last verified: 2018-03

Locations

IT (1)