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Clinical Trial Results:
Phase II trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH

Summary
EudraCT number	2018-000249-38
Trial protocol	GB
Global end of trial date	30 Apr 2021

Results information
Results version number	v1(current)
This version publication date	05 Mar 2023
First version publication date	05 Mar 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

R118439

ISRCTN number

US NCT number

NCT03737344

WHO universal trial number (UTN)

Sponsor organisation name

The University of Manchester

Sponsor organisation address

Oxford Road, Manchester, United Kingdom, M13 9PT

Public contact

Mohammed Zubair, University of Manchester , clinicaltrials@manchester.ac.uk

Scientific contact

Mohammed Zubair, University of Manchester , clinicaltrials@manchester.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

26 Jan 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

15 Feb 2021

Global end of trial reached?

Yes

Global end of trial date

30 Apr 2021

Was the trial ended prematurely?

Yes

Main objective of the trial

To determine whether interleukin-1 receptor antagonist (IL-1Ra (Anakinra / Kineret®)) reduce subacute perihaematomal oedema after intracerebral haemorrhage (ICH).

Protection of trial subjects

Side effects vary from patient to patient and all patients will be monitored closely and given appropriate medication to reduce side effects. Patients are informed of common side effects, risks and potential benefits of the trial in the Participant Information Sheet. Patients are asked to inform their medical team of any changes in their health, whether or not they think it is related to the medication. Investigators may ask patients to stop treatment or might reduce the dose of the drugs should they have any unexpected side effects or other illnesses which occur as a result of treatment. Any SAEs and SUSARs will be reported in line with GCP and Trust reporting requirements. Changes in the emerging safety profile of Anakinra (as detailed in the Investigator’s brochure) or any finding in this clinical trial will be monitored and patients will receive amended Participant Information Sheets and be asked to reconsent to the trial as and when required.

Background therapy

The care for all patients in the trial will be identical to the standard care pathway which will continue as normal including acute management of anticoagulant reversal, blood pressure lowering, intensive or high dependency care, rehabilitation, and clinical follow-up. No treatment will be withheld as a result of participating in the trial and participation will not affect clinical care.

Evidence for comparator

The prototypical, proinflammatory cytokine IL-1 plays a key role in the early damaging inflammatory response in the brain and inhibiting IL-1 leads to a reduction in damage in diverse experimental acute brain injuries including ischaemic stroke, excitotoxicity, traumatic brain injury, and ICH. We have recently shown that IL-1 alpha (IL-1α), IL-1 beta (IL-1β) and IL-1Ra are all present in high concentrations in serial haematoma fluid collected from acute ICH patients taking part in the MISTIE III trial. IL-1 is also rapidly upregulated in perihaematomal brain tissue from animal models of ICH and from ICH patients. The naturally occurring IL-1 blocker, IL-1Ra (Kineret®), is expressed at almost undetectable levels in healthy brain. A randomised, controlled, phase 2 trial of an intravenous (IV) infusion of IL-1Ra in acute stroke undertaken at Salford Royal NHS Foundation Trust (SRFT), demonstrated a significant reduction in inflammatory markers as well as reversal of stroke-related peripheral immunosuppression. More recently, it has become apparent that IL-1 has detrimental actions in both the brain and systemically in animal models of cerebral ischaemia, suggesting that IL-1 blocking treatments may not need to cross the blood-brain barrier to confer benefit in ischaemic stroke and prompting the use of much lower subcutaneous (SC) doses of IL-1Ra. A further randomised controlled phase 2 trial of SC IL-1Ra (100 mg BD for 3 days) tested this approach in 80 ischaemic stroke patients at SRFT has also demonstrated a significant reduction in plasma IL-6 and CRP. A single-centre, randomised, controlled phase 2 trial of SC IL-1Ra (100 mg OD for 5 days) in 20 patients with severe traumatic brain injury has shown IL-1Ra to be safe in this pathology, and penetrated in to plasma and brain extracellular fluid. A reduction in macrophage-derived chemoattractant within the brain of IL-1Ra treated patients was detected by microdialysis.

Actual start date of recruitment

15 Mar 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 25

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Patients with acute intra-cerebral haemorrhage were recruited for the trial. Patients with ICH recruited from Hyper Acute Stroke Units (HASUs) in the UK. Adults admitted to a participating centre with a clinical diagnosis of acute ICH also considered for trial participation.

Screening details

Patients with spontaneous, non-traumatic, supratentorial ICH with no underlying macrovascular or neoplastic cause admitted to a participating centre within 8 hours of symptom onset.

Period 1 title

Baseline

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst

Are arms mutually exclusive

Yes

Placebo

Arm description

Subcutaneous injection of matched placebo

Arm type

Placebo

Investigational medicinal product name

Placebo (Manufactured by Sobi AB)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Solution for injection , Subcutaneous use

Dosage and administration details

Subcutaneous injection of 100mg matched placebo (manufactured by Sobi AB) prepared in 0.67mL prefilled syringe for single use. Administered as soon as possible after randomisation. Continued twice daily (with a minimum of 8h and a maximum of 16h between doses) for up to 3 days (6 doses) from onset of symptoms or until discharge from the treating centre (whichever sooner).

Anakinra

Arm description

Subcutaneous injection of Anakinra

Arm type

Experimental

Investigational medicinal product name

Anakinra

Investigational medicinal product code

Other name

Kineret®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injection of 100mg Interleukin-1 receptor antagonist (IL-1Ra) Kineret® (Anakinra) prepared in 0.67mL prefilled syringe for single use. Administered as soon as possible after randomisation. Continued twice daily (with a minimum of 8h and a maximum of 16h between doses) for up to 3 days (6 doses) from onset of symptoms or until discharge from the treating centre (whichever sooner).

Number of subjects in period 1	Placebo	Anakinra
Started	11	14
Completed	11	14

Period 2 title

72 Hours

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst

Are arms mutually exclusive

Yes

Placebo

Arm description

Subcutaneous injection of matched placebo

Arm type

Placebo

Investigational medicinal product name

Placebo (Manufactured by Sobi AB)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Solution for injection , Subcutaneous use

Dosage and administration details

Anakinra

Arm description

Subcutaneous injection of Anakinra

Arm type

Experimental

Investigational medicinal product name

Anakinra

Investigational medicinal product code

Other name

Kineret®

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Number of subjects in period 2	Placebo	Anakinra
Started	11	14
Completed	11	12
Not completed	0	2
Adverse event, serious fatal	-	1
Consent withdrawn by subject	-	1

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Subcutaneous injection of matched placebo

Reporting group title

Anakinra

Reporting group description

Subcutaneous injection of Anakinra

Reporting group values	Placebo	Anakinra	Total
Number of subjects	11	14	25
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	4	6	10
From 65-84 years	6	6	12
85 years and over	1	2	3
Gender categorical
Units: Subjects
Female	6	6	12
Male	5	8	13
Ethnicity
Units: Subjects
White	9	12	21
Mixed	0	0	0
Asian / Asian British	1	0	1
Black / Black British	1	2	3
Chinese	0	0	0
Other	0	0	0
Premorbid mRS (modified Rankin Scale)
Units: Subjects
0 No Residual Symptoms	7	12	19
1 No significant disability	3	0	3
2 Slight disability	0	0	0
3 Moderate disability	1	2	3
4 Moderately severe disability	0	0	0
5 Severe disability	0	0	0
6 Unable to determine	0	0	0
Glasgow Coma Score Classification
Units: Subjects
Mild (14-15)	1	1	2
Moderate (9-13)	1	4	5
Severe (3-8)	9	9	18
NIHSS on admission/baseline
Units: Subjects
Minor (1-4)	5	1	6
Moderate (5-15)	4	8	12
Moderate-severe (16-20)	2	3	5
Severe (21-40)	0	2	2
Intraventricular haemorrhage
Units: Subjects
Yes	1	4	5
No	10	10	20
Haematoma location
Units: Subjects
Deep	8	7	15
Lobar	3	7	10
Hypertension
Units: Subjects
Yes	5	7	12
No	5	7	12
Unknown	1	0	1
Type 1 Diabetes
Units: Subjects
Yes	0	0	0
No	11	14	25
Type 2 Diabetes
Units: Subjects
Yes	1	0	1
No	10	14	24
Atrial fibrillation
Units: Subjects
Yes	3	3	6
No	1	0	1
Missing	7	11	18
Mechanical heart valve
Units: Subjects
Yes	0	0	0
No	4	3	7
Unknown	7	11	18
Venous thromboembolism
Units: Subjects
Yes	1	0	1
No	3	3	6
Missing	7	11	18
Use of antithrombotic drugs
Units: Subjects
Aspirin	0	0	0
Dipyridamole (Asasantin, Persantin)	0	0	0
Clopidogrel	0	0	0
Warfarin	0	3	3
Sinthrome	0	0	0
Rivaroxaban	2	0	2
Apixaban	2	0	2
Edoxaban	0	0	0
Dabigaltran	0	0	0
Other	0	0	0
None of the above	7	11	18
Time between onset and arrival in hospital
Units: Hours
median (full range (min-max))	1.8 (1.1 to 4.8)	1.6 (0.9 to 5.6)	-
Systolic Blood Pressure
Units: millimetres of mercury (mmHg)
arithmetic mean (standard deviation)	158.7 ± 22.3	160.7 ± 30.7	-
ICH volume
Units: ml
median (inter-quartile range (Q1-Q3))	5.5 (2.1 to 10.9)	12.6 (1.4 to 41.8)	-

End points

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Reporting group title

Placebo

Reporting group description

Subcutaneous injection of matched placebo

Reporting group title

Anakinra

Reporting group description

Subcutaneous injection of Anakinra

Reporting group title

Placebo

Reporting group description

Subcutaneous injection of matched placebo

Reporting group title

Anakinra

Reporting group description

Subcutaneous injection of Anakinra

Primary: Oedema extension distance (OED) at 72 hours

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End point title

Oedema extension distance (OED) at 72 hours

End point description

Oedema extension distance (OED) at 72 hours. Calculated as a derivative from The volume of perihaematomal oedema (PHO vol) and of the haematoma (ICH vol)

End point type

Primary

End point timeframe

Oedema extension distance (OED) at 72 hours from Baseline

End point values	Placebo	Anakinra	Placebo	Anakinra
Number of subjects analysed	11	14	11	13
Units: derived value (decimal)
arithmetic mean (standard deviation)
Mean (descriptive)	0.7 ± 0.6	1.0 ± 0.9	1.4 ± 1.2	1.7 ± 1.3
Mean change (72hr - baseline) (Descriptive)	0.6 ± 0.7	0.6 ± 0.7	0.6 ± 0.7	0.6 ± 0.7

ANCOVA of OED

Statistical analysis description

The primary analysis was an analysis of covariance (ANCOVA) which adjusted for baseline value of OED. Analyses conducted using 95% confidence intervals. No formal adjustments made for multiplicity as there is a single primary analysis. Given small sample size, interpretation largely descriptive with no hypothesis testing.

Comparison groups

Placebo v Anakinra

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

Method

Parameter type

Mean difference (final values)

Point estimate

-0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.74

upper limit

0.51

Notes
[1] - Primary analysis conducted under the principle of intention to treat and analysis of covariance adjusted for baseline value of OED.

Adverse events

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Timeframe for reporting adverse events

adverse event monitoring performed during the study treatment period. Further clinical assessments for safety monitoring at baseline, before the 2nd Investigational Medicinal Product (IMP) administration, on Day 4 and on Day 30 post randomisation.

Assessment type

Non-systematic

Dictionary name

Uncoded

Dictionary version

Reporting group title

Anakinra

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	Anakinra	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 14 (35.71%)	1 / 11 (9.09%)
number of deaths (all causes)	1	0
number of deaths resulting from adverse events	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Incidental bladder lesion
Additional description: Incidental bladder lesion
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardiac Arrhythmia
Additional description: Cardiac Arrhythmia
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Inflammatory Amyloid Angiopathy
Additional description: Inflammatory Amyloid Angiopathy
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intracerebral Hemorrhage
Additional description: Intracerebral Hemorrhage
subjects affected / exposed	2 / 14 (14.29%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large left basal ganglia bleed
Additional description: Large left basal ganglia bleed
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
Aspiration Pneumonia
Additional description: Aspiration Pneumonia
subjects affected / exposed	2 / 14 (14.29%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary Emboli
Additional description: Pulmonary Emboli
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypernatremia
Additional description: Hypernatremia
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Anakinra	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	2 / 14 (14.29%)	3 / 11 (27.27%)
Nervous system disorders
Sciatica
Additional description: Sciatica
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1
Seizure
Additional description: Seizure
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)
occurrences all number	1	0
General disorders and administration site conditions
Pyrexia
Additional description: Pyrexia
subjects affected / exposed	1 / 14 (7.14%)	0 / 11 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Aspiration Pneumonia
Additional description: Aspiration Pneumonia
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1
Skin and subcutaneous tissue disorders
Rash
Additional description: Rash
subjects affected / exposed	0 / 14 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

07 May 2019

SA01 - Removal of Stoke as a study site. Addition of Aberdeen as a study site.

11 Sep 2019

SA02 - Addition of 'pre notification pack' for 3 month follow up where the patient was consented via representative. Removal of pre IMP requirement for blood samples (excluding 1st sample)

17 Mar 2020

SA03 - Addition of study sites. Extension to the recruitment period. Change to the IMP administration window and update to exclusion criteria. Formatting change to ICF and typographical correction on GP Letter. Update to SmPC.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
Phase II trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Oedema extension distance (OED) at 72 hours

Primary: Oedema extension distance (OED) at 72 hours

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: Phase II trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Oedema extension distance (OED) at 72 hours

Primary: Oedema extension distance (OED) at 72 hours

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Phase II trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH