Tocilizumab in anti-TNF refractory patients with juvenile idiopathic arthritis (JIA) associated uveitis

ISRCTN	ISRCTN95363507
DOI	https://doi.org/10.1186/ISRCTN95363507
EudraCT/CTIS number	2015-001323-23
Secondary identifying numbers	19096

Submission date: 10/06/2015
Registration date: 10/06/2015
Last edited: 10/07/2023

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Musculoskeletal Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Juvenile idiopathic arthritis (JIA) is a form of arthritis that develops in children under 16. The cause of the disease is unknown. Symptoms include inflammation, pain and swelling of the joints. There are a number of forms of JIA, including oligoarticular JIA, polyarticular JIA and systemic onset JIA. Eye problems are common and include uveitis, a condition where there is swelling of the middle layer of the eye. Symptoms of uveitis include painful, red eyes, blurred vision, floaters and loss of peripheral vision. It is not a common condition but is still a leading cause of visual impairment in the UK. Here, we want to conduct a study to test whether adding tocilizumab to methotrexate (MTX) treatment will prevent the serious complications, such as glaucoma, cataracts and detached retina that can occur from uncontrolled uveitis in children with JIA. We wish to test the response rate to tocilizumab in combination with MTX and determine whether further research into this treatment for severe, refractory uveitis should be done.

Who can participate?
Children aged between 2-18 years with JIA and severe uveitis who have not responded or are not getting better on anti -TNF therapy (drugs such as adalimumab and infliximab)

What does the study involve?
All children taking part in this study are given tocilizumab injections every 2 weeks or 3 weeks as well as MTX treatment. The dosage for each child is calculated according to their body weight. Response to the treatment is reviewed after 3 months.

What are the possible benefits and risks of participating?
The NHS and its patients would benefit from this trial because patients will be the first worldwide to have access to this novel biological agent within the context of a combined hospital clinic with ophthalmologists and paediatric rheumatologists. Tocilizumab may affect the immune system (your body’s natural defences) and you may be more likely to get infections. Tocilizumab can also increase cholesterol levels, which will be monitored during the course of the study at each visit. Some other common side effects of Tocilizumab are
a cough or a sore throat, a blocked or runny nose, a headache or dizziness, mouth ulcers, conjunctivitis, high blood pressure, weight gain or swollen ankles, skin rashes, infections or itching, stomach irritation (gastritis), inflammation around the drip/ injection site.

Where is the study run from?
Six NHS hospitals in the UK

When is the study starting and how long is it expected to run for?
August 2015 to January 2018

Who is funding the study?
Arthritis Research UK

Who is the main contact?
Mr Ben Hardwick

Study website

Contact information

Mr Ben Hardwick
Scientific

The University of Liverpool
Department of Biostatistics
1st floor Duncan Building
Daulby Street
Liverpool
L69 3GA
United Kingdom

ORCID ID	0000-0003-1050-5777

Study information

Study design	Non-randomised; Interventional; Design type: Treatment
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use contact details to request a participant information sheet
Scientific title	A phase II trial of tocilizumab in anti-TNF refractory patients with JIA associated uveitis
Study acronym	APTITUDE
Study objectives	This study aims to test whether adding tocilizumab to methotrexate treatment for children with severe uveitis will enable us to prevent the serious complications that can occur from uncontrolled uveitis in children with juvenile idiopathic arthritis (JIA).
Ethics approval(s)	NRES Committee London - South East, ref: 15/LO/0771
Health condition(s) or problem(s) studied	Topic: Children, Ophthalmology, Musculoskeletal disorders; Subtopic: All Diagnoses, Eye (all Subtopics), Musculoskeletal (all Subtopics); Disease: All Diseases, Non-inflammatory Joint Disorders, Other
Intervention	All participants will receive tocilizumab injections every 2 weeks or every 3 weeks (dependent upon weight) of tocilizumab alongside methotrexate (MTX) treatment. The dosage will be calculated based on patient body weight. Study Entry : Registration only
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	Tocilizumab
Primary outcome measure	The primary endpoint is response to treatment. Response to treatment is defined as per SUN criteria as a 2 step decrease in the level of inflammation (anterior chamber cells) or decrease to zero between baseline (prior to trial treatment initiation) and after 12 weeks of treatment.
Secondary outcome measures	1. Safety, tolerability and compliance 1.1. Adverse events (AEs), serious adverse events (SAEs) and Adverse Events of Special Interest (AESI) 1.2. Laboratory parameters (haematological and biochemical analysis and urinalysis) 1.3. Participant diaries and dosing records will determine tolerability and compliance throughout the trial treatment period 2.Use of Corticosteroids over duration of study period and throughout follow up, including: 2.1. Total oral corticosteroid dose 2.2. Reduction in and rate of systemic corticosteroid dose from entry dose 2.3. Topical corticosteroid use (frequency) compared to usage at registration. 3. Optic and Ocular 3.1. Visual acuity measured by Age-appropriate LogMar assessment 3.2. Number of participants with resolution of associated optic nerve or macular oedema (as assessed by slit lamp biomicroscopy or optical coherence tomography (OCT)). 3.3. Number of patients who are able to reduce topical or systemic agents for ocular hypertension 3.4. Number of participants with disease control (defined as zero cells, with topical treatment at 12 weeks treatment visit and 24 weeks treatment visit.) 3.5. Number of participants entering disease remission (defined as zero cells, without topical treatment at 12 and 24 weeks treatment visit) 3.6. Duration of sustaining inactive disease (zero cells, with or without topical treatment.) 3.7. Failure to reduce eye drops to 2 drops/day by or at the 12 weeks visit 4. Quality of Life assessment (Childhood Health Questionnaire (CHQ), Childhood Health Assessment Questionnaire (CHAQ)) 5. American College of Rheumatology (ACR) Pedi core set criteria: at ACR30, ACR50, ACR70, ACR90 and ACR100 levels 6. Number participants requiring change in biologic / Disease-modifying anti-rheumatic drugs (DMARDs) therapy due to disease flare of their arthritis or failure to respond to treatment for their arthritis 7. Number of participants undergoing flare of arthritis, in remissions on and off medication of their JIA and with minimum disease activity
Overall study start date	01/02/2015
Completion date	01/04/2019

Eligibility

Participant type(s)	Patient
Age group	Child
Lower age limit	2 Years
Upper age limit	18 Years
Sex	Both
Target number of participants	Planned Sample Size: 22; UK Sample Size: 22
Total final enrolment	22
Key inclusion criteria	1. Children and young people aged at least 2 and 18 years fulfilling ILAR diagnostic criteria for JIA (all subgroups that have uveitis) 2. At the time of trial screening the participant must have active anterior uveitis, defined as a “sustained grade of cellular infiltrate in anterior chamber of SUN criteria grade =1+ or more during the preceding 6 weeks treatment 3. Participants must have failed MTX (minimum dose of 10mg/m2, with a maximum dose of 20mg/m2 and not to exceed 25mg/participant) The participant must have been on MTX for at least 12 weeks and have been on a stable dose of MTX for 4 weeks prior to screening visit 4. Participants must have failed an anti TNF agent (including etanercept, infliximab, golimumbab, certolizumab pegol or adalimumab) and have been on at least one antiTNF agent regardless of dose for at least 12 weeks at any time previously 5. If a patient has received previous treatment with any of the following biologic agents, these must have been discontinued according to the following timelines prior to registration: Infliximab 8 weeks prior to registration: 5.1. Etanercept 2 weeks prior to registration 5.2. Adalimumab 4 weeks prior to registration 5.3. Abatacept 8 weeks prior to registration 5.4. Canakinumab 20 weeks prior to registration 5.5. Rilonacept 6 weeks prior to registration 5.6. Anakinra 1 week prior to registration If a patient has been on another biologic agent not listed above then please contact the trial team for appropriate washout period 6. Written informed consent of participant or parent/legal guardian, and assent where appropriate. 7. Participant and parent/legal guardian willing and able to comply with protocol requirements. 8. For participants of reproductive potential (males and females), use of a reliable means of contraception throughout their trial participation (abstinence is an acceptable method of contraception as long as this is the usual and preferred lifestyle of the patient) 9. Post pubertal females must have a negative serum pregnancy test within 10 days prior to registration 10. Able to commence trial treatment within 2 weeks of the screening visit Target Gender: Male & Female; Upper Age Limit 18 years ; Lower Age Limit 4 years
Key exclusion criteria	1. Uveitis without a diagnosis of JIA 2. Currently on tocilizumab or has previously received tocilizumab. 3. Participation in another clinical trial of investigational medicinal product within the last 4 weeks or 5 serum half lives(whichever is longer) 4. More than 6 topical steroid eye drops per day per eye at time of screening 5. For patients on prednisone or prednisone equivalent, change of dose within 30 days prior to registration 6. For patients on prednisone or prednisone equivalent with a dose >0.2mg/kg per day 7. No intraocular injection of disease modification agents including steroids and antiVEGF within 6 months prior to registration. 8. No intraocular surgery for previous 12 weeks or expected/panned for duration of study. 9. Lack of recovery from recent surgery or surgery < 6 weeks at the time of registration 10. Intraocular pressure = 25mm Hg at time of screening. 11. On antiglaucoma medications 12. No disease modifying immunosuppressive drugs, other than MTX in the 4 weeks prior to registration 13. History of active tuberculosis of less than 6 months treatment or untreated latent TB (a test for latent tuberculosis infection (LTBI) must be performed within twelve weeks prior to registration. 14. Latent TB not successfully treated for at least 4 weeks prior to registration 15. Autoimmune, rheumatic disease or overlap syndrome other than JIA. 16. Females who are pregnant, lactating, or intending to become pregnant during trial 17. Known human immunodeficiency virus infection or other condition characterized by a compromised immune system 18. Any history of alcohol or drug abuse within 6 months prior to registration 19. Any active acute, subacute, chronic, or recurrent bacterial, viral, systemic fungal, infection or any major episode of infection requiring hospitalisation or treatment with IV antibiotics within 4 weeks of registration or treatment with oral antibiotics within 2 weeks of registration 20. History of reactivation or new onset of a systemic infection such as herpes zoster or Epstein-Barr virus within 2 months prior to registration 21. Hepatitis B surface antigen or hepatitis C antibody positivity or chronic viral or autoimmune hepatitis 22. History of concurrent serious gastrointestinal disorders 23. Evidence of current serious uncontrolled concomitant cardiovascular (including hyperlipidemia), nervous system,pulmonary (including obstructive pulmonary disease), renal and hepatic disease 24. History of or current cancer or lymphoma 25. Persistently poorly controlled severe hypertension (>95th percentile for height / age) 26. Uncontrolled diabetes mellitus 27. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies 28. No live attenuated vaccines (including seasonal nasal flu vaccine, varicella vaccine for shingles or chickenpox, MMR or MMRV, oral polio vaccine and vaccines for yellow fever, measles, mumps or rubella) 4 weeks prior to registration, throughout the duration of the trial and for 8 weeks following the last dose of study drug 29. Immunization with a live/attenuated vaccine within 4 weeks prior to registration 30. Previous treatment with any cell depleting therapies, including investigational agents or approved therapies (e.g.CAMPATH, antiCD4, antiCD5, anti CD3, antiCD19 and antiCD20) 31. Treatment with intravenous gamma globulin or plasmapheresis within 24 weeks of registration 32. Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation 33. Any significant medical or surgical condition that would risk the patient’s safety or their ability to complete the trial 34. Any psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial 35. Demonstrations of clinically significant deviations from the following laboratory parameters: 35.1 Serum creatinine > 1.5 × the upper limit of normal (ULN) for age and sex 35.2. AST or ALT > 1.5 × the ULN for age and sex 35.3. Total bilirubin > 1.3 mg/dL (>23 µmol/L) 35.4. Platelet count < 150 × 103/µL (< 150,000/mm3) 35.5. Hemoglobin < 7.0 g/dL (< 4.3 mmol/L) 35.6. White blood cell (WBC) count < 5,000/mm3 (< 5.0 × 109/L) 35.7 Neutrophil count < 2,500/mm3 (< 2.5 × 109/L)
Date of first enrolment	01/08/2015
Date of final enrolment	01/01/2018

Locations

Countries of recruitment

England
United Kingdom

Study participating centres

Bristol Royal Hospital for Children (Lead Centre)

Bristol
BS2 8BJ
United Kingdom

Great Ormond Street Hospital

London
WC1N 3JH
United Kingdom

Alder Hey Children’s Hospital

Liverpool
L12 2AP
United Kingdom

Southampton Children’s Hospital

Southampton
SO16 6YD
United Kingdom

Great North Children’s Hospital

Newcastle
NE1 4LP
United Kingdom

Sheffield Children’s Hospital

Sheffield
S10 2TH
United Kingdom

Sponsor information

University Hospitals Bristol NHS Foundation Trust
Hospital/treatment centre

Research & Development
Upper Maudlin Street
Bristol
BS2 8AE
England
United Kingdom

"ROR"	https://ror.org/04nm1cv11

Funders

Funder type

Charity

Arthritis Research UK
Private sector organisation / Other non-profit organizations

Location: United Kingdom

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not expected to be made available
Publication and dissemination plan	The Uniform Requirements for Manuscripts Submitted to Biomedical Journals (http://www.icmje.org/) will be respected. All publications shall include a list of participants, and if there are named authors, these should include the trial’s Chief Investigator(s), Statistician(s) and Trial Manager(s) involved at least. If there are no named authors (i.e. group authorship) then a writing committee will be identified that would usually include these people, at least. The ISRCTN allocated to this trial should be attached to any publications resulting from this trial.
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol article	protocol	27/02/2018	20/03/2019	Yes	No
Results article	results	07/02/2020	15/04/2020	Yes	No
HRA research summary			28/06/2023	No	No
Statistical Analysis Plan		27/02/2018	10/07/2023	No	No

Editorial Notes

10/07/2023: Statistical analysis plan added.
15/04/2020: The following changes have been made:
1. Publication reference added.
2. The total final enrolment number has been added from the reference.
20/03/2019: Publication reference added.