Supplementary appendix

Transcription

1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Ruperto N, Martini A. Current and future perspectives in the management of juvenile idiopathic arthritis. Lancet Child Adolesc Health 2018; published online Feb 6.

2 Supplementary Table 1: Interventional studies in juvenile idiopathic arthritis sponsored by pharmaceutical companies or investigator s initiated studies. This table contains also the trial title. Studies are listed in alphabetical order by drug. More information could be found by entering the NTC number at Trial title Drug (route) Target Indication* Study Status NCT number SPONSORED TRIALS An Observational Registry of Abatacept in Patients With Juvenile Idiopathic Arthritis A Study of Canakinumab in Patients With Systemic Juvenile Idiopathic Arthritis or Hereditary Periodic Fevers Who Participated in the CACZ885G2301E1, CACZ885G2306 or CACZ885N2301 Studies ß-SPECIFIC 4 Patients: Study of Pediatric EffiCacy and Safety with FIrst-line Use of Canakinumab (ß- SPECIFIC 4) A Repeated Dose-finding Study of Sarilumab in Children and Adolescents With Systemic Juvenile Idiopathic Arthritis (s) An Open-label, Ascending, Repeated Dose-finding Abatacept (iv, sc) CTL4-Ig Poly Observational, cohort, prospective Canakinumab (sc) IL-1 Systemic ; periodic fevers 1 Recruiting Bristol Myers and Squibb NCT Phase III Recruiting Novartis NCT Canakinumab (sc) IL-1 Systemic Phase III Recruiting Novartis NCT Sarilumab (sc) IL-6 Systemic Interventional Recruiting Sanofi NCT Sarilumab (sc) IL-6 Poly Phase II Recruiting Sanofi NCT

3 Trial title Drug (route) Target Indication* Study Status NCT number Study of Sarilumab in Children and Adolescents With Polyarticularcourse Juvenile Idiopathic Arthritis (pc) Extension Study Evaluating the Safety and Efficacy of Subcutaneous Tocilizumab (RoActemra/Actemra) Administration in Systemic and Polyarticular- Course Juvenile Idiopathic Arthritis A Study of Decreased Dose Frequency in Participants With Systemic Juvenile Arthritis Who Experience Laboratory Abnormalities During Treatment With RoActemra/Actemra (Tocilizumab) Efficacy Study Of Tofacitinib In Pediatric Population Long-Term Safety Study Of Tofacitinib In Patients With Juvenile Idiopathic Arthritis Tocilizumab (sc) IL-6 Poly ; Phase I Recruiting Roche NCT Tocilizumab (iv) IL-6 Phase IV Recruiting Roche NCT Tofacitinib (oral) IL-6 Poly Phase III, Interventional randomized Tofacitinib (oral) JAK Poly Phase III, Interventional Recruiting Pfizer NCT Recruiting Pfizer NCT

4 Trial title Drug (route) Target Indication* Study Status NCT number INVESTIGATOR S INITIATED STUDIES TRIALS Oxidation Rates of the Different Substrates During Exercise in Children and Adolescents With Juvenile Idiopathic Arthritis. Casecontrol Study and Cases Treated / Cases Not Treated With Anti-TNFα (OSE- ) anti-tnfα (sc, iv) TNF Poly Interventional, nonrandomized Recruiting University Hospital, Clermont- Ferrand NCT Start Time Optimization of Biologics in Polyarticular (STOP- ) Biologics (sc, iv) Several targets Poly Observational, prospective Recruiting Hackensack University Medical Center NCT Pharmacovigilance in Juvenile Idiopathic Arthritis Patients Treated With Biologic Agents and/or Methotrexate (PharmaChild) Biologics (sc, iv) Several targets Observational, prospective Recruiting Istituto Giannina Gaslini NCT Intranasal Dexmedetomidine Sedation During Intra-articular Joint Injections in Pediatric Population Dexmedetomidine (in) α2 adrenergic receptors Phase IV Recruiting University of Oulu NCT

5 Trial title Drug (route) Target Indication* Study Status NCT number Dietary Supplement: Interventional, Recruiting NCT VSL#3 (oral) Randomized Probiotic Treatment in Juvenile Idiopathic Arthritis () (PERMAJI) Assistance Publique - Hôpitaux de Paris Treatment Tapering in With Inactive Disease (AJIBIOREM) Etanercept (sc), Adalimumab(sc), Abatacept (iv), Tocilizumab (iv) TNF TNF, CTL4Ig IL-6 Poly Phase III Recruiting Assistance Publique - Hôpitaux de Paris NCT Study of Methotrexate Given to Juvenile Idiopathic Arthritis Patients Based on Pharmacogenomics and Pharmacometrics Methotrexate (oral, sc) Folic acid antagonist therapeutic drug monitoring Recruiting Guangzhou Women and Children's Medical Center NCT *indication derived primarily from trial title iv: intravenous, sc: subcutaneous; in: intranasal; IL: interleukin 4

6 Supplementary Table 2: List of pediatric investigation plans (PIP) in juvenile idiopathic arthritis. This table contains also the trial title. Studies are listed in alphabetical order by drug. More information could be found by entering the at Source Trial title Drug (route) Target Indication Study Open-label study to evaluate pharmacokinetics, treatment response and safety of abatacept administered subcutaneously in patients with juvenile idiopathic arthritis Abatacept (sc) CTL4Ig Bristol-Myers Squibb Pharma EEIG EMEA PIP02-10-M02 Open-label, multiple dose study to evaluate the pharmacokinetics, safety, and tolerability and to confirm the dosing regimen of ABT-494 in children with active polyarticular course Randomised, placebo-controlled, double-blind withdrawal study to evaluate the safety and efficacy of ABT-494 in children with active polyarticular course Upadacitinib (oral) Upadacitinib (oral) JAK poly AbbVie Ltd EMEA PIP01-14 JAK poly AbbVie Ltd EMEA PIP01-14 Randomised, placebo-controlled, double-blind withdrawal study to evaluate the safety and efficacy of multiple doses of ABT-494 in children with active Upadacitinib (oral) JAK AbbVie Ltd EMEA PIP01-14 A double-blind, placebo-controlled, multicentre study of the efficacy and safety of the human anti-tnf monoclonal antibody adalimumab in paediatric patients with enthesitis-related arthritis. Adalimumab (sc) TNF ERA DBPC AbbVie Ltd EMEA PIP01-08-M06 5

7 A multicentre, randomised, double-blind, placebo-controlled study of the safety, efficacy, and pharmacokinetics of the human anti-tnf monoclonal antibody adalimumab in children with polyarticular juvenile idiopathic arthritis. Compassionate use study of adalimumab in children from 2 to less than 4 Years old or age 4 and above weighing less than 15 kg with active juvenile idiopathic arthritis (). Adalimumab (sc) TNF poly DBPC AbbVie Ltd EMEA PIP01-08-M06 Adalimumab (sc) TNF AbbVie Ltd EMEA PIP01-08-M06 Double-blind, randomised placebo-controlled study to evaluate safety and efficacy in children with with open label extension phase Open-label pharmacokinetic and safety study in children with with 50 weeks open label extension Open-label pharmacokinetic and safety study in children with juvenile idiopathic arthritis () from 6 to less than 18 years of age Apremilast (oral) PDE4 DBPC Celgene Europe Apremilast (oral) PDE4 Celgene Europe Apremilast (oral) PDE4 Celgene Europe EMEA PIP02-11-M02 EMEA PIP02-11-M02 EMEA PIP02-11-M02 Double-blind, randomised, placebo-controlled safety, tolerability, and efficacy study of baricitinib in children from 2 years to less than 18 years with active -associated uveitis. Baricitinib (oral) JAK associated uveitis DBPC Eli Lilly & Company Limite EMEA PIP01-11-M01 6

8 Double-blind, randomised, withdrawal, placebocontrolled study to evaluate safety and efficacy of baricitinib in children from 2 years to less than 18 years of age with juvenile idiopathic arthritis (). Baricitinib (oral) JAK poly Eli Lilly & Company Limite EMEA PIP01-11-M01 Double-blind, randomised, withdrawal, placebocontrolled study to evaluate safety, efficacy and pharmacokinetics of baricitinib in children from 1 year to less than 18 years of age with juvenile idiopathic arthritis (s). Baricitinib (oral) JAK Eli Lilly & Company Limite EMEA PIP01-11-M01 A multi-centre, open label, repeated dose range finding study to evaluate the safety, tolerability, immunogenicity and pharmacokinetics of canakinumab given subcutaneously in paediatric subjects with active juvenile idiopathic arthritis. Canakinumab (sc) IL-1 Novartis Europharm EMEA PIP02-08-M06 A randomized, double-blind, placebo controlled, single-dose study to assess the efficacy of canakinumab in patients from 2 years to less than 20 years of age with Systemic Juvenile Idiopathic Arthritis (s) and active manifestations. Canakinumab (sc) IL-1 DBPC Novartis Europharm EMEA PIP02-08-M06 7

9 A randomized, double-blind, placebo controlled, withdrawal study of flare prevention of canakinumab in patients from 2 years to less than 20 years of age with Systemic Juvenile Idiopathic Arthritis (s) and active manifestations. Canakinumab (sc) IL-1 Novartis Europharm EMEA PIP02-08-M06 An open-label extension study canakinumab in patients with Systemic Juvenile Idiopathic Arthritis (s) and active manifestations. Canakinumab (sc) IL-1 Novartis Europharm EMEA PIP02-08-M06 Multicentre, open-label study to assess pharmacokinetics (PK), safety and efficacy of certolizumab pegol in children and adolescents with moderate to severe active polyarticularcourse juvenile idiopathic arthritis Certolizumab pegol (sc) TNF poly UCB Pharma SA EMEA PIP02-12-M01 Multicentre, randomised, single-blind, placebocontrolled study to assess the efficacy and safety of certolizumab pegol in children and adolescents with juvenile idiopathic arthritisassociated uveitis Certolizumab pegol (sc) TNF associated uveitis DBPC UCB Pharma SA EMEA PIP02-12-M01 An open-label study to evaluate pharmacokinetics, safety and treatment effect of clazakizumab in children from 1 to less than 18 years old with juvenile idiopathic arthritis (IM133-P73). Clazakizumab (sc) IL-6 Bristol-Myers Squibb International Corporation EMEA PIP

10 Multi-centre randomised withdrawal placebo controlled study to evaluate safety and efficacy in children from 2 to less than 18 years old with -associated uveitis Clazakizumab (sc) IL-6 associated uveitis Bristol-Myers Squibb International Corporation EMEA PIP01-12 Randomised, double blind, multicentre, placebo controlled, withdrawal study to evaluate pharmacokinetics, safety and efficacy of clazakizumab in children from 2 to less than 18 years old with polyarticular juvenile idiopathic arthritis (IM133-P74). Clazakizumab (sc) IL-6 poly Bristol-Myers Squibb International Corporation EMEA PIP01-12 Open-label multicentre extension study for evaluation of long-term efficacy and safety in patients with RA and involved in previous studies (Study ). Etanercept (sc) TNF poly Wyeth Europa EMEA PIP01-08-M03 Open-label nonrandomised multicentre registry study of children with polyarticular course or onset from 1 year to less than 18 years for evaluation of long-term safety of etanercept compared to patients receiving methotrexate (Study ). Etanercept (sc) TNF poly ; Wyeth Europa EMEA PIP01-08-M03 9

11 Single-treatment open-label multicentre study of patients with oligoarticular from 2 years to less than 18 years and psoriatic arthritis or enthesitis related arthritis from 12 to less than 18 years to evaluate efficacy and safety of etanercept in comparison with historical control cohort of placebo treated patients (Study 0881A WW). Etanercept (sc) TNF poly ; ERA; JPsA Wyeth Europa EMEA PIP01-08-M03 Fostamatinib Fostamatinib (oral) SYK Waiver* waiver Astrazeneca AB EMEA PIP01-11 Multicentre, open-label, dose finding, preliminary safety and efficacy study in patients with polyarticular course of not adequately responding to the standard treatment. Givinostat (oral) histone deacetylase inhibitor poly Italfarmaco SpA EMEA PIP01-09 Multicentre, randomised, withdrawal placebocontrolled efficacy and safety study in patients with Polyarticular course not adequately responding to standard treatment. Givinostat (oral) histone deacetylase inhibito poly Italfarmaco SpA EMEA PIP01-09 Double-blind, randomised withdrawal, multicentre; two phase placebo controlled study to evaluate pharmacokinetics, safety and efficacy of golimumab in combination with methotrexate in children with from 2 years to less than 18 years of age with inadequate response to methotrexate Golimumab (sc) TNF Janssen Biologics B.V. EMEA PIP01-08-M04 10

12 Multicentre, double-blind, randomized, placebocontrolled, safety, tolerability, pharmacokinetic and efficacy study of subcutaneous Ixekizumab in children with juvenile idiopathic arthritis Ixekizumab (sc) IL-17A DBPC Eli Lilly & Company EMEA PIP01-10-M02 Multicentre, double-blind, randomized, placebocontrolled, safety, tolerability, PK, and efficacy study of Ixekizumab in children with juvenile idiopathic arthritis with active features (s) Ixekizumab (sc) IL-17A DBPC Eli Lilly & Company EMEA PIP01-10-M02 A double-blind, multicentre, placebo controlled randomised-withdrawal study to evaluate the efficacy and safety of JNJ in children from 2 to less than 18 years old with. An open label study to evaluate the pharmacokinetics, safety and tolerability of JNJ in children from 2 to less than 12 years old with juvenile idiopathic arthritis (). Toreforant (oral) H 4 R Janssen Cilag International NV Toreforant (oral) H 4 R Janssen Cilag International NV EMEA PIP01-13 EMEA PIP01-13 An open-label, single-arm study to assess the safety and efficacy of JNJ in children from 2 to less than 18 years of age with refractory active anterior uveitis associated with juvenile idiopathic arthritis (). Toreforant (oral) H 4 R associated uveitis Janssen Cilag International NV EMEA PIP

13 Double-blind, multicentre, randomizedwithdrawal study to evaluate the safety and efficacy of JNJ in paediatric patients from 2 to less than 18 years with polyarticular (p) and enthesitis-related arthritis (ERA) including a vaccination response substudy. Peficitinib (oral) JAK poly ; ERA EMEA PIP01-13 Double-blind, multicentre, randomizedwithdrawal study to evaluate the safety and efficacy of JNJ in paediatric patients from 2 to less than 18 years with -onset (s). Peficitinib (oral) JAK EMEA PIP01-13 Open-label, exploratory, single-arm study to assess the safety and efficacy of JNJ in subjects with refractory active anterior uveitis associated with juvenile idiopathic arthritis. Peficitinib (oral) JAK associated uveitis EMEA PIP01-13 Pharmacokinetic study to evaluate the PK of JNJ in paediatric patients with polyarticular juvenile idiopathic arthritis (p) or (s) from 2 to less than 12 years including the evaluation of safety and tolerability. Peficitinib (oral) JAK poly ; EMEA PIP01-13 Double-blind, randomised withdrawal, placebocontrolled study in children from 2 to less than 18 years of age with polyarticular ; followed by longterm extension. Olokizumab (sc) IL-6 poly UCB Pharma S.A. EMEA PIP

14 Randomised, double-blind, placebo-controlled study in children from 1 to less than 18 years of age with with open label extension. Olokizumab (sc) IL-6 DBPC UCB Pharma S.A. EMEA PIP01-11 Double-blind, randomised, placebo-controlled withdrawal study to evaluate the clinical benefit, safety, pharmacokinetics and immunogenicity of sarilumab in children from 1 to less than 18 years of age with treatment-resistant juvenile idiopathic arthritis (s). Sarilumab (sc) IL-6 Sanofi-Aventis Recherche & Développement EMEA PIP01-10 Double-blind, randomised, placebo-controlled withdrawal study to evaluate the clinical benefit, safety, pharmacokinetics and immunogenicity of sarilumab in children from 2 to less than 18 years of age with treatment-resistant polyarticular course juvenile idiopathic arthritis (p). Sarilumab (sc) IL-6 poly Sanofi-Aventis Recherche & Développement EMEA PIP01-10 Open-label, ascending 12-week repeated dosefinding study of sarilumab in children from 1 to less than 18 years of age with juvenile idiopathic arthritis (s). Sarilumab (sc) IL-6 Sanofi-Aventis Recherche & Développement EMEA PIP01-10 Open-label, ascending 12-week repeated dosefinding study of sarilumab in children from 2 to less than 18 years of age with polyarticular course juvenile idiopathic arthritis (p). Sarilumab (sc) IL-6 poly Sanofi-Aventis Recherche & Développement EMEA PIP

15 Double-blind, randomised, placebo controlled three-part withdrawal study to evaluate efficacy and safety of secukinumab in children with juvenile idiopathic arthritis (enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA)). Secukinumab (sc) IL-27 ERA; JPsA Novartis Europharm EMEA PIP02-09-M03 A double-blind, parallel group study to evaluate pharmacokinetics, pharmacodynamics, safety and short term efficacy of CNTO 136 in patients with polyarticular and. Sirukumab (sc) IL-6 poly ; DBPC EMEA PIP01-10-M02 A double-blind, parallel group study to evaluate pharmacokinetics, pharmacodynamics, safety and short term efficacy of CNTO 136 in patients with polyarticular and. Sirukumab (sc) IL-6 poly ; DBPC EMEA PIP01-10-M02 A double-blind, randomised-withdrawal, multicentre study for evaluation of the safety and efficacy of CNTO 136 as a treatment for patients with polyarticular (p) and patients with ERA who have failed anti-tnf alpha therapy. Sirukumab (sc) IL-6 poly ; ERA EMEA PIP01-10-M02 A double-blind, randomised-withdrawal, multicentre study for evaluation of the safety and efficacy of CNTO 136 as a treatment for patients with polyarticular (p) and patients with ERA who have failed anti-tnf alpha therapy. Sirukumab (sc) IL-6 poly ; ERA EMEA PIP01-10-M02 14

16 A double-blind, randomised-withdrawal, multicentre study for evaluation of the safety and efficacy of CNTO 136 as a treatment for patients with (s). Sirukumab (sc) IL-6 EMEA PIP01-10-M02 A double-blind, randomised-withdrawal, multicentre study for evaluation of the safety and efficacy of CNTO 136 as a treatment for patients with (s). Sirukumab (sc) IL-6 EMEA PIP01-10-M02 Open label multi-centre study to investigate pharmacokinetics, pharmacodynamics, efficacy and safety of tocilizumab following subcutaneous administration in patients aged from 1 to less than 18 years old with juvenile idiopathic arthritis. Tocilizumab (sc) IL-6 Roche Registration EMEA PIP01-08-M07 Open label multi-centre study to investigate pharmacokinetics, pharmacodynamics, efficacy and safety of tocilizumab following subcutaneous administration in patients with polyarticular juvenile idiopathic arthritis. Open-label, multi-centre withdrawal study to evaluate the efficacy and safety of tocilizumab in patients aged from 2 years to less than 18 years with active polyarticular-course juvenile idiopathic arthritis, with open-label extension. Tocilizumab (sc) IL-6 poly Roche Registration Tocilizumab (sc) IL-6 poly Roche Registration EMEA PIP01-08-M07 EMEA PIP01-08-M07 15

17 Randomised, double-blind, placebo-controlled, parallel-group, 2-arm 12-week study to evaluate the efficacy and safety of tocilizumab in patients aged from 2 years to less than 18 years with active juvenile idiopathic arthritis with 92-week single-arm open-label extension. Tocilizumab (sc) IL-6 DBPC Roche Registration EMEA PIP01-08-M07 Multiple dose pharmacokinetic study in children from 2 to less than 18 years of age with juvenile idiopathic arthritis Tofacitinib (oral) JAK Pfizer EMEA PIP01-09-M06 Randomised double blind placebo controlled study to evaluate safety and efficacy of CP- 690,550 in children from 2 to less than 18 years old with juvenile idiopathic arthritis with active features Tofacitinib (oral) JAK Pfizer EMEA PIP01-09-M06 Randomised withdrawal double blind placebo controlled study to evaluate efficacy and safety of CP-690,550 in children from 2 to less than 18 years old with polyarticular course juvenile idiopathic arthritis (i.e. extended oligoarthritis, RF+/RF- polyarthritis and arthritis without features), enthesitis related arthritis and psoriatic arthritis Tofacitinib (oral) JAK Poly Pfizer EMEA PIP01-09-M06 16

18 Double-blind, placebo controlled randomised withdrawal study of the safety and efficacy of ustekinumab in patients with polyarticular. Ustekinumab (sc) IL-12, IL- 23 poly International NV EMEA PIP03-11-M02 *indication derived primarily from trial title : juvenile idiopathic arthritis; ERA: enthesitis related arthritis; JPsA; juvenile psoriatic arthritis DBPC: double-blind-placebo-controlled; : double-blind-placebo-controlled-randomized-withdrawal; : open label iv: intravenous, sc: subcutaneous; IL: interleukin. PDE4: phosphodiesterase 4; H 4 R: hystamine 4 receptor antagonist *Note a waiver has been granted for fostamatinib (the drug will not be studied for ) 17