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BMC Rheumatol. 2018 Feb 27;2:4. doi: 10.1186/s41927-018-0010-2. eCollection 2018.

A phase II trial protocol of Tocilizumab in anti-TNF refractory patients with JIA-associated uveitis (the APTITUDE trial).

Author information

1
1University Hospitals Bristol NHS Foundation Trust & Bristol Medical School, University of Bristol, Bristol, UK.
2
2Bristol Eye Hospital, Bristol, UK.
3
3School of Clinical Sciences, University of Bristol, UCL Institute of Ophthalmology and National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology, Bristol, London UK.
4
4Clinical Trials Research Centre, Department of Biostatistics, University of Liverpool, Liverpool, UK.
5
5Department of Women's and Children's, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
6
6Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.

Abstract

Background:

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of intraocular inflammation (uveitis). In the initial stages of mild-moderate inflammation uveitis is asymptomatic. Most children with mild-moderate uveitis are managed on topical steroid drops with or without systemic methotrexate (MTX). When children with moderate-severe uveitis are refractory to MTX, monoclonal anti-tumour necrosis factor agents have been trialled, interim analysis data showed positive results. However, several children with severe recalcitrant disease or non-responsive to anti-tumour necrosis factor agents remain and are at greater risk of significant ocular complications and visual loss. Further evidence of alternative therapies is needed with evidence of a potential role of anti-interleukin-6 agents in the management of severe refractory uveitis.

Methods:

The trial will be conducted following a two-stage Simon design. The trial will register at least 22 patients aged 2 to 18 years with active JIA-associated uveitis, who have taken MTX for at least 12 weeks and have failed an anti-TNF agent. It will take place in 7 centres across the UK. All participants will be treated for 6 months, with follow up of 9 months from registration. Participants will receive a stable dose of MTX and those weighing ≥30 kg will be dosed with 162 mg of Tocilizumab every 2 weeks and participants weighing < 30 kg dosed with 162 mg of Tocilizumab every 3 weeks. Primary outcome is treatment response at 12 weeks. Adverse events will be collected up to 30 calendar days following treatment cessation.

Discussion:

This is a novel adaptive design study of subcutaneous IL-6 inhibition in anti-TNF refractory JIA associated uveitis which will be able to determine if further research should be conducted. This is the first trial to look at ophthalmology outcomes in the efficacy of Tocilizumab in uveitis.This is the first paediatric clinical trial to assess the clinical effectiveness and safety of tocilizumab with MTX in JIA associated uveitis.

Trials registration:

The Trial is registered on the ISRCTN registry (ISRCTN95363507) on the 10/06/2015 and EU Clinical Trials Register on the 03/07/2015 (EudraCT Number: 2015-001323-23).

KEYWORDS:

Juvenile Idiopathic Arthritis; Methotrexate; Ophthalmology; Paediatric; Rheumatology; Safety; Tocilizumab; Uveitis

Conflict of interest statement

AR is a Paediatric Rheumatologist at Bristol Royal Hospital for Children and Royal National Hospital for Rheumatic Diseases, Bath, UK. AD is Professor of Ophthalmology, University of Bristol, Duke Elder Professor of Ophthalmology, UCL Institute of Ophthalmology and Joint Director of Research for Moorfields Eye Hospital and Institute of Ophthalmology, UK. CG is a Consultant Ophthalmologist at the Bristol Eye Hospital, Bristol, UK. BH is a Trial Co-ordinator at the Clinical Trials Research Centre, University of Liverpool, Liverpool, UK. HH is Head of Trial Management at the Clinical Trials Research Centre, University of Liverpool, Liverpool, UK. AJ is a Senior Statistician at the Clinical Trials Research Centre, University of Liverpool, Liverpool, UK. RL is a Clinical Lecturer in Ophthalmology at the Bristol Eye Hospital, Bristol, UK. AM is a Statistician at the Clinical Trials Research Centre, University of Liverpool, Liverpool, UK. MB is Brough Chair and Professor of Child Health, University of Liverpool, Director of the Arthritis Research UK Experimental Arthritis Treatment Centre for Children, Director of the NIHR Alder Hey Experimental Arthritis Treatment Centre, academic lead for the Clinical Academic Department of Paediatric Rheumatology at Alder Hey Children’s NHS Foundation Trust, Liverpool, UK and Specialty Cluster Lead of the NIHR CRN National Coordinating Centre Hub including the National Specialties of Children and Musculoskeletal research.Full ethical approval has been gained from the National Research Ethics Service Committee London – South East (15/LO/0771). Full approval has also been gained from the Medicines and Healthcare Products Regulatory Agency (European Clinical Trials Database number 2015–001323-23). This trial recruits minors and young people under the age of 16 years. Informed consent procedures reflected the legal and ethical requirements to obtain valid informed consent for this population. Prior written informed consent is required for all trial participants. In obtaining and documenting informed consent, the investigator complies with applicable regulatory requirements and adheres to Good Clinical Practice and to the ethical principles that have their origin in the Declaration of Helsinki.Not applicableThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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