Condition category
Eye Diseases
Date applied
25/03/2020
Date assigned
14/04/2020
Last edited
06/07/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
Autoimmune uveitis is a term for several rare eye diseases in which the body’s own immune system causes sight-threatening damage to the light sensitive retina at the back of the eye. Uveitis causes sight loss from inflammation inside the eye, damage to blood vessels in the retina or leakage of fluid into the central, most sensitive area of the retina. Two in 10,000 people are at risk of serious sight loss from uveitis. Usual treatment for autoimmune uveitis involves low dose steroids and one or two other drugs to reduce inflammation. Unfortunately, many patients do not respond to or tolerate usual treatment, or they need high dose steroids to control the uveitis. Long term high dose steroids increase the risk of heart attack, stroke, and infection and affect physical and mental health. Adalimumab is a drug that targets chemicals released by inflamed tissue, neutralising their damage to the body. This study aims, first, to identify patients who are most likely to benefit from adalimumab. Then, in patients who are successfully treated with adalimumab and low dose steroids, a randomised controlled trial will be conducted to compare adalimumab and placebo.

Who can participate?
Adults over 18 years, with sight-threatening autoimmune non-infectious uveitis and is prescribed corticosteroids greater than 5.0 mg/day.

What does the study involve?
All eligible patients who consent will be given adalimumab for a 16-week trial period, if necessary in combination with low dose of steroids; these patients will include those with impaired vision due to uveitis, requiring high dose steroids to bring the disease under control, and those with better vision but who require high dose steroids to keep the uveitis under control. Over the 16 weeks, doctors will aim to reduce the steroid dose to a low level that should not cause side effects.
Then, patients who are successfully treated with adalimumab and low dose steroids will enter the main study. They will be given adalimumab or a dummy treatment, in combination with their other medications (including low dose steroids). Chance will determine who receives which treatment and neither patients nor their eye doctors will know. Regular eye examinations, tests and questionnaires will be used to assess how well patients are doing. This part of the study, which will treat and follow up patients for 12 to 30 months, will find out whether adalimumab is better at preventing recurrence of uveitis than the dummy treatment and whether adalimumab is cost-effective compared to the dummy treatment.

What are the possible benefits and risks of participating?
The study cannot promise any benefits to participants but the information we get from this study will help improve the treatment of people with uveitis. Patients who are currently not eligible for adalimumab on the NHS could benefit from being prescribed it as part of this study. Participants might be able to reduce their dose of corticosteroids if taking adalimumab. It is possible, but cannot be guaranteed, that participants will eventually be able to stop taking at least one of their other immunosuppression medications.
There is a small risk of permanent eye damage from uveitis if participants are allocated to the placebo group, although the risk is the same as if they were receiving normal NHS care and not taking adalimumab. To minimise this risk, participants will be closely monitored with frequent enough hospital visits that if their condition relapses it should be picked up by their eye doctor before permanent uveitis damage occurs. In both group, injections under the skin can be mildly sore, and participants can get a reaction at the injection site. Adalimumab can cause side effects, although not everybody gets them. Most side effects are mild to moderate. However, some may be serious and require treatment. Side effects may occur up to four months or more after the last adalimumab injection.

Patient and public involvement
Patients with uveitis have contributed to the study from the start, helping to: design the protocol to ensure it applies to uveitis patients who may benefit; co-authoring the lay summary; helping to draft the application, providing feedback on the trial design and participating in a national survey to assess support for the study. They will continue to contribute in these ways and provide support to patients. The research team includes eye doctors and researchers with expertise in doing eye studies.

Where is the study run from?
Bristol Trials Centre (UK)

When is the study starting and how long is it expected to run for?
November 2020 to March 2024

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
Dr Abby O’Connell
astute-trial@bristol.ac.uk

Trial website

http://cteu.bris.ac.uk/our-studies/?trialType=Ophthalmology#5206

Contact information

Type

Public

Primary contact

Dr Abby O'Connell

ORCID ID

http://orcid.org/0000-0001-7598-927X

Contact details

Bristol Trials Centre
University of Bristol
Level 7 Queens Building
Bristol Royal Infirmary
Bristol
BS2 8HW
United Kingdom
+44 (0)1173422987
astute-trial@bristol.ac.uk

Additional identifiers

EudraCT number

2020-000754-97

ClinicalTrials.gov number

Nil known

Protocol/serial number

IRAS 271051, CPMS 45139

Study information

Scientific title

The ASTUTE trial: Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness: a randomized controlled trial

Acronym

ASTUTE

Study hypothesis

The trial hypothesises that adalimumab reduces the hazard of treatment failure in patients with autoimmune non-infectious uveitis (ANIU), after weaning of corticosteroids (CS) to less than or equal to 5 mg/day in a treatment run-in period.

Ethics approval

Current ethics approval as of 08/06/2020:
Approved 03/06/2020, South Central - Oxford B Research Ethics Committee (Level 3, Block B, Whitefriars, Lewins Mead, Bristol, BS1 2NT, UK; +44 (0)2071048046; oxfordb.rec@hra.nhs.uk), ref: 20/SC/0153

_____

Previous ethics approval:
Approval pending, South Central - Oxford B Research Ethics Committee (Level 3, Block B, Whitefriars, Lewins Mead, Bristol, BS1 2NT, UK; +44 (0)2071048046; oxfordb.rec@hra.nhs.uk), ref: 20/SC/0153

Study design

Double-blind parallel multi-centre randomized placebo-controlled trial with open-label treatment run-in period

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Autoimmune non-infectious uveitis

Intervention

All participants start on open-label adalimumab for 16 weeks.

Participants who respond to adalimumab are randomised to adalimumab or placebo for up to 128 weeks.

Randomisation is concealed and done by an online computer program after data to confirm eligibility is recorded.

Adalimumab (Imraldi) and placebo
Dose: 80mg followed by 40mg every 2 weeks, starting 1 week after the initial dose.

During the treatment run-in phase, data is collected at week 4, week 8, and week 16.
During the RCT phase, data is collected at 12 weeks, 24 weeks, 36 weeks, 48 weeks, 64 weeks, 80 weeks, 96 weeks, 112 weeks, and 128 weeks.

Intervention type

Drug

Phase

Phase IV

Drug names

Adalimumab

Primary outcome measure

Time to the first treatment failure (TF) assessed at each visit after randomisation (12 weeks, 24 weeks, 36 weeks, 48 weeks, 64 weeks, 80 weeks, 96 weeks, 112 weeks, and 128 weeks)
i.e. TF may occur in either eye and may be triggered by incident ANIU in an eye that did not previously have ANIU. TF is defined as a composite of standard criteria reflecting clinical decision-making, including visual acuity and clinical signs of active inflammation which have been used successfully in other ANIU trials. Participants will be assessed for TF at each visit after randomisation. Any of the following criteria in one or both eyes, where applicable, will constitute TF:
i. greater than or equal to 15 letter decrease in best-corrected visual acuity (BCVA), compared to BCVA measured by an optometrist masked to treatment allocation at the 16-week treatment run-in (TRI) visit
ii. new active inflammatory chorioretinal lesions
iii. greater than 20% increase in central macular thickness (CMT), compared to CMT at the 16 week TRI timepoint
iv. onset or worsening of retinal vasculitis
v. 2-step worsening of vitreous haze cf. compared to best score at either the 8- or 16-week TRI visit
vi. prescription by a masked clinician of greater than 5mg/day corticosteroids to maintain disease remission (i.e. to avert relapse before any of the above criteria for manifest active disease (i-v))

Secondary outcome measures

At 12 weeks, 24 weeks, 36 weeks, 48 weeks, 64 weeks, 80 weeks, 96 weeks, 112 weeks, and 128 weeks unless otherwise noted.
1. Individual treatment failure (TF) components, assessed at each trial visit
2. Retinal morphology (OCT; macular and retinal nerve fibre layer), assessed at each trial visit
3. Adverse events, assessed at each trial visit
4. Health-related quality of life measured using the EQ-5D-5L questionnaire at the start of treatment run-in (TRI), at 16 weeks immediately before randomisation, then 12-weekly after randomisation up to week 48 and 16-weekly thereafter
5. Patient-reported symptoms of side-effects at each trial visit after starting the TRI and at any interim attendance prompted by an adverse event
6. Patient-reported visual function at the start of TRI, at 16 weeks immediately before randomisation, 12-weekly up to week 48 and 16 weekly thereafter
7. Employment status at the start of TRI, at 16 weeks immediately before randomisation, 12-weekly up to week 48 and 16 weekly thereafter
8. Resource use during follow-up after randomisation, at the start of TRI, at 16 weeks immediately before randomisation, 12-weekly up to week 48 and 16 weekly thereafter

Overall trial start date

01/04/2020

Overall trial end date

31/03/2024

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Aged 18 years or over
2. Sight-threatening ANIU and is prescribed CS greater than 5.0 mg/day
3. Women must have a negative pregnancy test and be willing to use effective contraception for the duration of the participation in the trial and for 5 months after, or be surgically sterile or post-menopausal for > 12 months
4. Able to provide informed consent

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

400

Participant exclusion criteria

Current exclusion criteria as of 08/06/2020:
1. Participant has controlled ANIU and is maintained on CS ≤5.0mg/day at the time of screening
2. Participant has untreated or active tuberculosis
3. Participant has severe infection, sepsis or opportunistic infection
4. Participant has uncontrolled glaucoma
5. Participant has multiple sclerosis
6. Participant is HIV positive
7. Participant has hepatitis B or hepatitis C
8. Participant has syphilis
9. Participant has Lyme disease
10. Participant has Behcet's disease
11. Participant has heart failure (NYHA III/IV;
12. Participant has been diagnosed with cancer <5 years ago
13. Participant is undergoing monitoring for recurrence of cancer/tumour growth where their oncologist has concern that a TNFalpha inhibitor would be contraindicated
14. Participant is taking another biologic drug
15. Participant has taken an anti-TNF drug within the previous 90 days (anakinra and abatacept are contraindicated)
16. Participant has an ocular CS implant within the previous 12 months or an intravitreal steroid injection within the previous 3 months
17. Participant is pregnant
18. Participant has a known allergy or hypersensitivity to adalimumab or any of its excipients
19. Participant is taking part in another interventional study

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Previous exclusion criteria:
1. Controlled ANIU and is maintained on CS less than or equal to 5.0 mg/day at the time of screening
2. Untreated or active tuberculosis
3. Severe infection, sepsis or opportunistic infection
4. Uncontrolled glaucoma
5. Multiple sclerosis
6. HIV positive
7. Hepatitis B or hepatitis C
8. Behcet’s disease
9. Heart failure (NYHA III/IV)
10. No history of varicella or does not have varicella antibodies
11. Taking another biologic drug
12. Taken an anti-TNF drug within the previous 90 days (anakinra and abatacept are contraindicated)
13. Ocular CS implant within the previous 12 months or an intravitreal steroid injection within the previous 3 months
14. Pregnant
15. Known allergy or hypersensitivity to adalimumab or any of its excipients
16. Taking part in another interventional study

Recruitment start date

01/11/2020

Recruitment end date

30/04/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

University Hospitals Bristol NHS Foundation Trust
Trust Headquarters Marlborough Street
Bristol
BS1 3NU
United Kingdom

Trial participating centre

John Radcliffe Hopsital
Oxford University Hospitals NHS Foundation Trust Headley Way
Oxford
OX3 9DU
United Kingdom

Trial participating centre

Royal Liverpool Hospital
Royal Liverpool and Broadgreen University Hospitals NHS Trust Prescot Street
Liverpool
L7 8XP
United Kingdom

Trial participating centre

Norfolk and Norwich University Hospital
Norfolk and Norwich University Hospitals NHS Foundation Trust Colney Lane
Norwich
NR4 7UY
United Kingdom

Trial participating centre

York Hospital
York Teaching Hospital NHS Foundation Trust Wigginton Road
York
YO31 8HE
United Kingdom

Trial participating centre

Leicester Royal Infirmary
University Hospitals of Leicester NHS Trust Infirmary Square
Leicester
LE1 5WW
United Kingdom

Trial participating centre

Queen Elizabeth Hospital
University Hospitals Birmingham NHS Foundation Trust Mindelsohn Way Edgbaston
Birmingham
B15 2GW
United Kingdom

Trial participating centre

University Hospital Coventry
University Hospitals Coventry and Warwickshire NHS Trust Clifford Bridge Road
Coventry
CV2 2DX
United Kingdom

Trial participating centre

Addenbrookes Hospital
Cambridge University Hospitals NHS Foundation Trust Hills Road
Cambridge
CB2 0QQ
United Kingdom

Trial participating centre

Queens Medical Centre
Nottingham University Hospitals NHS Trust Derby Road
Nottingham
NG7 2UH
United Kingdom

Trial participating centre

Southampton General Hospital
University Hospital Southampton NHS Foundation Trust Tremona Road
Southampton
SO16 6YD
United Kingdom

Trial participating centre

Manchester Royal Infirmary
Manchester University NHS Foundation Trust North Road
Manchester
M13 9WL
United Kingdom

Trial participating centre

St. James's University Hospital
Leeds Teaching Hospitals NHS Trust Beckett Street
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Moorfields Eye Hospital
Moorfields Eye Hospital NHS Foundation Trust 162 City Rd
London
EC1V 2PD
United Kingdom

Trial participating centre

Royal Surrey County Hospital
Royal Surrey County Hospital NHS Foundation Trust Egerton Road
Guildford
GU2 7XX
United Kingdom

Sponsor information

Organisation

University Hospitals Bristol NHS Foundation Trust

Sponsor details

Marlborough Street
Bristol
BS1 3NU
United Kingdom
+44 (0)1173420233
R&DSponsorship@UHBristol.nhs.uk

Sponsor type

Hospital/treatment centre

Website

http://www.uhbristol.nhs.uk/

Funders

Funder type

Government

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Results will be published in peer-reviewed medical journals and presented at professional conferences. Results will be disseminated via patient groups, on the trial web-page and publicised on social media. A summary of the results will be sent to participants who specify that they would like to receive them.

IPD sharing statement:
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. (Contact the chief investigator Prof Andrew Dick; Email: a.dick@bristol.ac.uk. Data will be made available after the trial outcomes paper is published in a peer-reviewed journal; applicants must provide an as a minimum a publicly available pre-specified protocol describing the purpose, methods and analysis of the secondary research; de-identified data will be available indefinitely; consent from participants for secondary use of data will be obtained; patient identifiable data will never be shared with third parties.

Intention to publish date

01/04/2024

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

06/07/2020: The recruitment end date was changed from 30/04/2021 to 30/04/2022. 08/06/2020: The following changes have been made: 1. The ethics approval has been updated. 2. The participant exclusion criteria have been changed. 25/03/2020: Trial’s existence confirmed by National Institute for Health Research (NIHR).