IL-1ra Dose-range Study for Moderate-to-severe TBI Patients (IL1ra)

A Randomised Double Blind Placebo Controlled Dose-range Study Using Placebo, 1.5g and 3.0g of Intravenous Recombinant Interleukin-1 Receptor Antagonist (Anakinra) for Patients With Moderate-to-severe TBI

Traumatic brain injury (TBI) is a common condition with high degree of morbidity and mortality (Hyder et al., 2007). Current treatment paradigms for TBI focus on mitigating secondary injury and maintaining cerebral physiology (Carney et al., 2016), however, there are currently no approved drugs that target the underlying conditions for patients suffering from TBI (Bullock et al., 1999). It is increasingly recognised that the innate inflammatory response to TBI may inflict injury (Lucas et al., 2006), and one of the most prominent mediators of inflammation in the injured brain is the Interleukin-1 (IL-1) receptor pathway (Allan et al., 2005). An endogenous antagonist to IL-1, is available in recombinant form (IL-1ra, Kineret), and is known to be safe in TBI (Helmy et al., 2014).

In order to fully understand, and potentially optimize, the effect of Kineret, the investigators wish to conduct a dose-response study by giving three cohorts (n=20 per group) either placebo (isotonic saline), 1.5g or 3.0g of active substance administered intravenously in a double-blind, randomized setting. The concentrations have in previous studies not been shown to present any side-effects (Singh et al., 2014). The drug will be provided within 12 hours after trauma. The goal will be to provide a dose-response effect on the cerebral inflammatory response. As secondary goals, the investigators will assess the brain damage by measuring proteins in blood and cerebrospinal fluid, functional outcome and inflammation in the brain using positron emission tomography.

Study Overview

• Status: Unknown
• Conditions: Traumatic Brain INjury
• Intervention / Treatment: Drug: Isotonic saline; Drug: Anakinra Prefilled Syringe

Detailed Description

Aim

The hypothesis is that an increasing dose of the anti-inflammatory drug recombinant human Interleukin-1 receptor antagonist (IL-1ra, Kineret) will modulate the inflammatory state of the traumatically injured brain, which will attenuate the injurious processes that occur following TBI.

Study Design

While different doses of Anakinra have been used in trials, there is no knowledge of what constitutes an optimized concentration of the drug. To address this limitation, the current study will be a dose-response study in a double blind randomised clinical fashion, using placebo (n=20), 1.5 g ("intermediate dose") or (n=20) and 3.0 g ("high dose")(n=20) of Anakinra provided the first 48 hours (drug/placebo administered initially as 500 mg infusion bolus and later as an 1g or 2.5g infusion for 48 hours). Thus, a total of n=60 patients will be included. Sample-size analyses have indicated that the number of patients is sufficient to detect differences in the inflammatory response as gauged with cytokine measurements using cerebral microdialysis.

As surrogate markers of outcome for these patients, several protein biomarkers of brain injury and proteins of the innate immune responses will be quantified using techniques called ELISA and multiplex assay technology. The investigators also wish to use radiological techniques, such as magnetic resonance imaging to study damages in white matter tracts in the brain and positron emission tomography to assess the degree of microglial activation. All these methods will be used to assess the potential benefit of the treatment vs placebo.

By this type of study design, it will minimize bias and confounders that may influence the study.

Patient Recruitment

Patients with a clinical diagnosis of severe and moderate TBI will be identified by the research team at the daily departmental neuro-critical care unit meeting. Patients meeting the inclusion criteria will be approached for consent/assent if conscious or if next of kin is present. If not, consent will be assumed as we know Anakinra to be safe and there is likely to be a narrow therapeutic window. With the current patient load at Addenbrooke's Hospital, Cambridge, the investigators deem it possible to recruit one patient per week, thus estimating that the recruiting phase will take approximately two years to complete.

Sampling

All the sampling will be conducted during the acute phase when the patient is unconscious in the neuro-critical care unit. Microdialysis probes are sampled hourly. To assess inflammatory activity in the brain, positron emission tomography will be performed within the first week and after 2-3 weeks. Magnetic resonance imaging will be performed the first 2-3 weeks and then after 6 months. To measure the patient's adaptive immune response to brain specific proteins, specialised auto-immunisation assays will be performed on patient blood at day 1-3 following injury as well as after 2-3 weeks.

During the intensive care phase, blood and cerebrospinal fluid will be sampled twice per day (approximately 3mL per sampling time per compartment, volumes that we do not deem harmful to the patient) and will be collected together with hourly microdialysate fluid samples the first 7 days from admission. Blood will also be sampled at an outpatient clinic follow up at 6 and 12 months following injury. Patient samples will be anonymised and stored at -80degC in the Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge before analysis.

It will not to be possible to measure cytokines, the drug and biomarkers from all microdialysis samples due to volume constraints. Moreover, we believe that a temporal resolution of 6 hours is probably adequate for the brain concentration of the drug while 12 hours is sufficient in serum. APP and tau will also be measured every 6 hours. The only parameter that will be hourly analysed in microdialysis is cytokine and chemokines through a luminex panel.

Clinical Follow-up

Patients will be followed up at a clinic visit at 6 and 12 months after trauma by questionnaire survey using standardised outcome measures in neurosurgical patients including the golden standard extended Glasgow Outcome Score and Short Form 36.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Adel Helmy, MA, MB BChir, FRCS, PhD; Phone Number: 00441223 216147; Email: adelhelmy@cantab.net
• Study Contact Backup: Name: Eric P Thelin, MD, PhD; Phone Number: 0046739365450; Email: thelin.eric@gmail.com

Study Locations

• United Kingdom
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
      • Cambridge University Hospital NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Suffer from a TBI, present with a Glasgow Coma Scale (GCS) of 3-13 and be deemed to be in need of neuro-critical care and intracranial monitoring for at least 72 hours.
2. Be aged 18-65
3. The first dose of Kineret (or placebo) must be provided within 12 hours after trauma.

Exclusion Criteria:

1. Head injury unlikely to survive 5 days (radiological evidence of above as judged by clinical team, bilateral fixed and dilated pupils).
2. Follow up not possible
3. Not suitable for insertion of cranial access device to monitor the brain (such as bleeding complications)
4. Active immunosuppression therapy (evidence of neutropenia, immunosuppression secondary to immunomodulatory medications, chemotherapy or radiation therapy in the 3 months preceding study entry)
5. Severe Renal Insufficiency or End Stage Renal Disease (defined as a creatinine clearance <30 ml/min)
6. Pregnancy/Nursing mothers
7. Known hypersensitivity to E. coli derived products
8. Administration of live vaccine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Isotonic saline administered as an injection and infusion	Drug: Isotonic saline; Placebo, administration as initially intravenous injection followed by a intravenous infusion; Other Names: Placebo
Experimental: 1.5 g Kineret; Kineret provided as a 500 mg injection followed by a 1g infusion.	Drug: Anakinra Prefilled Syringe; Administration as initially intravenous injection followed by a intravenous infusion; Other Names: Kineret
Experimental: 3.0 g Kineret; Kineret provided as a 500 mg injection followed by a 2.5g infusion.	Drug: Anakinra Prefilled Syringe; Administration as initially intravenous injection followed by a intravenous infusion; Other Names: Kineret

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Decrease of pro-inflammatory cytokines in brain extracellular fluid (ECF)	Decrease of Tumor necrosis factor alpha and interferon gamma cytokines in brain ECF	First 48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient outcome GOSe	Extended Glasgow Outcome Score (GOSe) assessments at 6 months and 1 year.	6 months and 12 months
Patient outcome SF36	Short Form - 36 (SF-36) assessments at 6 months and 1 year.	6 months and 12 months
Imaging outcome - PET-MRI	To determine degree of microglial activation globally and in the locality of the microdialysis catheter, using magnetic resonance imaging (MRI) in combination with positron emission tomography (PET) PK-11195 (an an isoquinoline carboxamide) ligand.	During the first 14 days
Imaging outcome - DTI-MRI	To determine degree of axonal injury globally and in the locality of the microdialysis catheter, using magnetic resonance imaging (MRI) in combination with diffuse tensor imaging (DTI).	During the first 14 days
Biochemical outcome - S100B	Concentrations of protein biomarkers of tissue fate, S100B in serum (µg/L) twice per day as well as after 6 months and 12 months.	During the first 7 days + at 6 months and 12 months
Biochemical outcome - NF-L	Concentrations of protein biomarkers of tissue fate, Concentrations of protein biomarkers of tissue fate, Neurofilament Light (NF-L) in serum (µg/L) twice per day as well as after 6 months and 12 months.	During the first 7 days
Biochemical outcome - Tau	Concentrations of protein biomarkers of tissue fate, microtubuli associated protein tau (tau) measured in microdialysis every 6 hours.	During the first 7 days
Biochemical outcome - APP	Concentrations of protein biomarkers of tissue fate, Amyloid Precursor Protein Beta (APP) associated protein tau measured in microdialysis every 6 hours.	During the first 7 days
Biochemical outcome - Autoreactivity versus MBP	Concentration of circulating T-cells with autoreactivity towards myelin basic protein (MBP) in serum.	During the first 7 days + at 6 months and 12 months
Monitoring outcome - ICP	Intracranial pressure (ICP, mmHg) during the neuro-critical care unit (NCCU) stay.	First 7 days
Monitoring outcome - CPP	Cerebral perfusion pressure (CPP, mmHg) during the NCCU stay.	First 7 days
Monitoring outcome - Cerebral Metabolism LPR	Cerebral metabolism, by measuring lactate:pyruvate ratio (LPR) in microdialysis.	First 7 days
Monitoring outcome - Brain tissue oxygenation	Brain tissue oxygen (mmHg).	First 7 days
Monitoring outcome - PRx	Derived variables of cerebral elastance (Pressure reactivity index, PRx).	First 7 days
Pharmacological outcome - Concentration of IL1ra in brain tissue	IL-1ra brain concentration (pg/ml), measured every 6 hours by cerebral microdialysis.	First week
Pharmacological outcome - Concentration of IL1ra in serum	IL-1ra serum concentration (pg/ml), measured every 12 hours.	First week
Side effects of the IL1ra	To study any potential side-effect of the drug, both known and unknown.	First week + up to 12 months follow-up

Collaborators and Investigators

• Sponsor: Adel Helmy
• Collaborators: Cambridge University Hospitals NHS Foundation Trust
• Investigators: Principal Investigator: Adel Helmy, MA, MB BChir, FRCS, PhD, University of Cambridge

Publications and helpful links

General Publications

• Helmy A, Guilfoyle MR, Carpenter KL, Pickard JD, Menon DK, Hutchinson PJ. Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial. J Cereb Blood Flow Metab. 2014 May;34(5):845-51. doi: 10.1038/jcbfm.2014.23. Epub 2014 Feb 26.
• Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and neuronal injury. Nat Rev Immunol. 2005 Aug;5(8):629-40. doi: 10.1038/nri1664.
• Bullock MR, Lyeth BG, Muizelaar JP. Current status of neuroprotection trials for traumatic brain injury: lessons from animal models and clinical studies. Neurosurgery. 1999 Aug;45(2):207-17; discussion 217-20. doi: 10.1097/00006123-199908000-00001.
• Carney N, Totten AM, O'Reilly C, Ullman JS, Hawryluk GW, Bell MJ, Bratton SL, Chesnut R, Harris OA, Kissoon N, Rubiano AM, Shutter L, Tasker RC, Vavilala MS, Wilberger J, Wright DW, Ghajar J. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017 Jan 1;80(1):6-15. doi: 10.1227/NEU.0000000000001432.
• Hyder AA, Wunderlich CA, Puvanachandra P, Gururaj G, Kobusingye OC. The impact of traumatic brain injuries: a global perspective. NeuroRehabilitation. 2007;22(5):341-53.
• Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol. 2006 Jan;147 Suppl 1(Suppl 1):S232-40. doi: 10.1038/sj.bjp.0706400.
• Singh N, Hopkins SJ, Hulme S, Galea JP, Hoadley M, Vail A, Hutchinson PJ, Grainger S, Rothwell NJ, King AT, Tyrrell PJ. The effect of intravenous interleukin-1 receptor antagonist on inflammatory mediators in cerebrospinal fluid after subarachnoid haemorrhage: a phase II randomised controlled trial. J Neuroinflammation. 2014 Jan 3;11:1. doi: 10.1186/1742-2094-11-1.

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2017
• Primary Completion (Anticipated): October 1, 2021
• Study Completion (Anticipated): October 1, 2021

Study Registration Dates

• First Submitted: December 7, 2016
• First Submitted That Met QC Criteria: December 15, 2016
• First Posted (Estimate): December 20, 2016

Study Record Updates

• Last Update Posted (Actual): May 8, 2017
• Last Update Submitted That Met QC Criteria: May 3, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Positron Emission Tomography; Magnetic Resonance Imaging; Traumatic brain injury; Microdialysis; Interleukin-1 receptor antagonist
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Brain Injuries, Traumatic; Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: CCTU0185

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No