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

NCT02997371 | Unknown Phase 2 DMC

• 1 other identifier: CCTU0185
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Traumatic Brain INjury

Keywords

Traumatic brain injury; Microdialysis; Interleukin-1 receptor antagonist; Magnetic Resonance Imaging; Positron Emission Tomography

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (17)

• Patient outcome GOSe

  6 months and 12 months

• Patient outcome SF36

  6 months and 12 months

• Imaging outcome - PET-MRI

  During the first 14 days

• Imaging outcome - DTI-MRI

  During the first 14 days

• Biochemical outcome - S100B

  During the first 7 days + at 6 months and 12 months

Study Arms (3)

Placebo

PLACEBO COMPARATOR

Isotonic saline administered as an injection and infusion

Drug: Isotonic saline

1.5 g Kineret

EXPERIMENTAL

Kineret provided as a 500 mg injection followed by a 1g infusion.

Drug: Anakinra Prefilled Syringe

3.0 g Kineret

EXPERIMENTAL

Kineret provided as a 500 mg injection followed by a 2.5g infusion.

Drug: Anakinra Prefilled Syringe

Interventions

Anakinra Prefilled Syringe DRUG

Administration as initially intravenous injection followed by a intravenous infusion

Also known as: Kineret

1.5 g Kineret; 3.0 g Kineret

Isotonic saline DRUG

Placebo, administration as initially intravenous injection followed by a intravenous infusion

Also known as: Placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Be aged 18-65
• The first dose of Kineret (or placebo) must be provided within 12 hours after trauma.

You may not qualify if:

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

Sponsors & Collaborators

• Adel Helmy: lead
• Cambridge University Hospitals NHS Foundation Trust: collaborator

Study Sites (1)

Cambridge University Hospital NHS Trust

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

Location

Related Publications (7)

• Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and neuronal injury. Nat Rev Immunol. 2005 Aug;5(8):629-40. doi: 10.1038/nri1664.

  PMID: 16034365 BACKGROUND

• 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.

  PMID: 10449064 BACKGROUND

• 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.

  PMID: 27654000 BACKGROUND

• 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.

  PMID: 24569690 BACKGROUND

• 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.

  PMID: 18162698 BACKGROUND

• 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.

  PMID: 16402109 BACKGROUND

• 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.

  PMID: 24383930 BACKGROUND

MeSH Terms

Conditions

Brain Injuries, Traumatic

Interventions

Interleukin 1 Receptor Antagonist Protein; Sodium Chloride

Condition Hierarchy (Ancestors)

Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Adel Helmy, MA, MB BChir, FRCS, PhD

  University of Cambridge

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Adel Helmy, MA, MB BChir, FRCS, PhD

CONTACT

00441223 216147; adelhelmy@cantab.net

Eric P Thelin, MD, PhD

CONTACT

0046739365450; thelin.eric@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MA, MB BChir, PhD, FRCS (SN)

Study Record Dates

• First Submitted: December 7, 2016
• First Posted: December 20, 2016
• Study Start: October 1, 2017
• Primary Completion: October 1, 2021
• Study Completion: October 1, 2021
• Last Updated: May 8, 2017

Record last verified: 2017-05

Locations

GB (1)