Clinical Trials Register

Summary
EudraCT Number:	2020-000754-97
Sponsor's Protocol Code Number:	OP/2017/6195
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2020-09-11
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2020-000754-97

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

ASTUTE Trial: Adalimumab versus placebo for the treatment of uveitis, an autoimmune eye disease.

A.3.2

Name or abbreviated title of the trial where available

The ASTUTE Trial

A.4.1

Sponsor's protocol code number

OP/2017/6195

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN31474800

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University Hospitals Bristol and Weston NHS Foundation Trust
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	National Institute for Health Research
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Bristol Trials Centre (CTEU) University of Bristol
B.5.2	Functional name of contact point	Dr Abby O'Connell
B.5.3	Address:
B.5.3.1	Street Address	Level 7 Queens Building, Bristol Royal Infirmary, University of Bristol
B.5.3.2	Town/ city	Bristol
B.5.3.3	Post code	BS2 8HW
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01173422987
B.5.6	E-mail	astute-trial@bristol.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Imraldi 40 mg solution for injection in pre-filled pen
D.2.1.1.2	Name of the Marketing Authorisation holder	Samsung Bioepis NL B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Imraldi 40 mg solution for injection in pre-filled pen
D.3.4	Pharmaceutical form	Solution for injection in pre-filled pen
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Adalimumab
D.3.9.1	CAS number	331731-18-1
D.3.9.3	Other descriptive name	N/A
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection in pre-filled pen
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Autoimmune non-infectious uveitis (ANIU)

E.1.1.1

Medical condition in easily understood language

Autoimmune uveitis (inflammation of the eye)

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10075690
E.1.2	Term	Autoimmune uveitis
E.1.2	System Organ Class	10015919 - Eye disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main aim is to compare the effectiveness and cost-effectiveness of adalimumab when used to treat patients with automimmune non-infectious uveitis who are taking less than or equal to 5mg of steroids per day and other immunomodulatory therapy drugs drugs, as required.

The primary outcome is the time to the first treatment failure (TF). Treatment failure is defined as:

i. greater than or equal to 15 letter decrease in best corrected visual acuity (BCVA), compared to BCVA at the 16 week treatment run-in stage; BCVA will be determined by an optometrist masked to treatment allocation.

ii. new active inflammatory chorioretinal lesions (review of fundus colour and autofluorescence images by masked clinician)

iii. greater than 20% increase in central macular thickness (CMT), compared to the CMT at the 16-week treatment run-in stage (CMT is a parameter that is measured by an automated algorithm when doing optical coherence tomography (OCT)).

iv. onset or worsening of retinal vasculiti

E.2.2

Secondary objectives of the trial

The objectives are:
1) To estimate differences between groups with respect to a range of secondary outcomes including: separate components of the composite treatment failure outcome (see A10, items i-vi), visual function, ocular and retinal signs of disease activity, health-related quality of life (HRQoL), resource use and costs and adverse events (AEs).

2) To estimate the cost-effectiveness of adalimumab compared to usual care.

3) To investigate associations between patient factors and ocular and retinal signs at the start of the treatment run-in with responder status at 16 weeks, and to explore emerging participant phenotypes associated with treatment failure during follow-up in the main trial.

Secondary outcomes include:
a) Individual treatment failure components, assessed at each trial visit;

b) Retinal morphology (optical coherence tomography; macular and retinal nerve fibre layer), assessed at each trial visit;

c) Adverse events, assessed at each trial visit;

d) Health-rela

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Additional blood samples will be collected for research purposes from consenting participants. Blood samples will be pseudonymised and processed into serum and DNA and stored frozen at the University of Oxford. The samples will be used in future ethically-approved studies to look for biomarkers of a response to adalimumab and other as yet unknown studies.

Research blood samples will be collected at the start of the treatment run-in, after 16 weeks/randomisation, at 48 weeks and 96 weeks post-randomisation and at any time-point that a participant meets the treatment failure criteria.

E.3

Principal inclusion criteria

Patients must:
(a) present with active sight-threatening ANIU in either or both eyes and who are taking oral prednisolone >5mg/day or being started on steroids >5mg/day, or

(b) those in remission taking >5mg/day of oral prednisolone and other immunomodulatory therapy drugs as required.

In the subgroup presenting with new active disease, remission will be induced with high dose oral prednisolone; oral prednisolone will be tapered to less than or equal to 5mg/day over 16 weeks in both groups. The treatment goal in the treatment run-in is the same for both groups, i.e. disease remission with less than or equal to 5mg/day oral prednisolone. If achieved by the end of the treatment run-in, participants will be eligible for randomisation.

To be eligible for the trial, including the 'treatment run-in', all of the following must apply:

1. Participant is aged 18 years or over;

2. Participant has: (a) active sight threatening ANIU (active inflammatory chorioretinal lesions OR abnormal central macular thickness (CMT) OR evidence of retinal vasculitis OR vitreous haze >0.5) and is being prescribed (already taking or being started on, if newly presenting with ANIU) oral prednisolone >5.0mg/day; OR (b) has controlled ANIU and is being prescribed oral prednisolone >5.0mg/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. Participant is able to provide informed consent.

* this includes: progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action, male or female condom with or without spermicide cap, diaphragm or sponge with spermicide, combined (eostrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation: (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, sexual abstinence.

E.4

Principal exclusion criteria

A participant may not enter the trial, including the 'treatment run-in' if any of the following apply:

1. Participant has controlled ANIU and is maintained on corticosteroids ≤5.0 mg/day at the time of screening;

2. Participant has systemic disease (whether associated with ANIU or not) that is being treated with steroids and requires >5mg/day oral prednisolone;

3. Participant has untreated or active tuberculosis;

4. Participant has severe infection, sepsis or opportunistic infection;

5. Participant has uncontrolled glaucoma;

6. Participant has multiple sclerosis;

7. Participant is HIV positive;

8. Participant has hepatitis B or hepatitis C

9. Participant has syphilis

10. Participant has Lyme disease

11. Participant has Behcet’s disease

12. Participant has toxoplasmosis chorioretinitis

13. Participant has heart failure (NYHA III/IV)

14. Participant has been diagnosed with cancer <5 years ago

15. Participant is undergoing monitoring for recurrence of cancer / tumour growth where their oncologist has concern that a TNFalpha inhibitor would be contraindicated

16. Participant is taking another biologic drug;

17. Participant has taken an anti-TNF drug within the previous 90 days (anakinra and abatacept are contraindicated);

18. Participant has had an Iluvien® implant within the previous 18 months and has controlled ANIU, or has had an Iluvien® implant within the previous 12 weeks regardless of whether ANIU is active or controlled;

19. Participant has had an Ozurdex® implant, or an intravitreal steroid injection, or periocular steroid within the previous 12 weeks regardless of whether ANIU is active or controlled;

20. Participant is pregnant;

21. Participant has a known allergy or hypersensitivity to adalimumab or any of its excipients;

22. Participant is taking part in another interventional study.

E.5 End points

E.5.1

Primary end point(s)

The primary outcome is the time to the first treatment failure (TF), assessed at the level of a participant, 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. Our definition of TF will modify the composite endpoint used in the VISUAL trials by: (i) excluding isolated anterior uveitis as a TF event (it can be treated effectively and safely with low dose, low frequency topical CS); and (ii) including a clinically important deterioration in central macular oedema (CMO) as a TF event, because it is an ANIU complication causing visual loss in a third of patients which has often been studied as a TF event in other trials of ANIU. 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 BCVA at the 16 week treatment run-in stage; BCVA will be determined by an optometrist masked to treatment allocation.

ii. new active inflammatory chorioretinal lesions (review of fundus colour and autofluorescence images by masked clinician)

iii. greater than 20% increase in central macular thickness (CMT), compared to the CMT at the 16-week treatment run-in stage (CMT is a parameter that is measured by an automated algorithm when doing optical coherence tomography (OCT)).

iv. onset or worsening of retinal vasculitis (masked clinician assessment of fundus fluoroscein angiogram)

v. 2 step worsening of vitreous haze compared to best vitreous haze category at 8- or 16-weeks during the treatment run-in (masked clinician assessment)

vi. prescription by a masked clinician of more than 5mg/day oral prednisolone to maintain disease remission (i.e. to prevent relapse before any of the above criteria (i-v) are met).
Prescription of more than 5mg/day prednisolone for a co-morbidity (e.g. rheumatic disease) where none of the other treatment failure criteria (i-v) have been met does not constitute treatment failure.

E.5.1.1

Timepoint(s) of evaluation of this end point

Treatment failure will be evaluated at 12, 24, 36 and 48 weeks post-randomisation and 16-weekly thereafter up to 128 weeks.

E.5.2

Secondary end point(s)

Secondary outcomes will include:

a) Individual TF components, assessed at each trial visit;

b) Retinal morphology (OCT; macular and retinal nerve fibre layer), assessed at each trial visit;

c) Adverse events, assessed at each trial visit;

d) Health-related quality of life measured using the EQ-5D-5L questionnaire at the start of treatment run-in, at 16 weeks immediately before randomisation, then 3-monthly after randomization up to month 12 and 4-monthly thereafter;

e) Patient-reported symptoms of side-effects at each trial visit after starting the treatment run-in and at any interim attendance prompted by an adverse event;

f) Patient-reported visual function at the start of treatment run-in, at 16 weeks immediately before randomisation, 3-monthly up to month 12 and 4-monthly thereafter;

g) Employment status at the start of treatment run-in, at 16 weeks immediately before randomisation, 3-monthly up to month 12 and 4-monthly thereafter;

h) Resource use during follow-up after randomisation, at the start of TRI, at 16 weeks immediately before randomisation, 3-monthly up to month 12 and 4-monthly thereafter .

E.5.2.1

Timepoint(s) of evaluation of this end point

a & b: Every 12 weeks post-randomisation up to 48 weeks, and 16-weekly thereafter.

c: From the start of the treatment run-in at every trial visit.

d, e, f & h: At the start of the treatment run-in and 16 weeks later plus, if enrolled in the RCT, every 12 weeks post-randomisation up to 48 weeks, and 16-weekly thereafter.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Cost effectiveness

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The trial will end for a participant after they have completed follow up for a minimum of 48 weeks up to a maximum of 128 weeks post-randomisation, or earlier if they withdraw from the study completely.

The end of the trial as a whole will be after all trial participants have completed follow up, all data queries have been resolved and the database has been locked.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1