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

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ClinicalTrials.gov Identifier: NCT02997371
Recruitment Status : Not yet recruiting
First Posted : December 20, 2016
Last Update Posted : May 8, 2017
Sponsor:
Collaborator:
Cambridge University Hospitals NHS Foundation Trust
Information provided by (Responsible Party):
Adel Helmy, University of Cambridge

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.


Condition or disease Intervention/treatment Phase
Traumatic Brain INjury Drug: Anakinra Prefilled Syringe Drug: Isotonic saline Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : October 2017
Estimated Primary Completion Date : October 2021
Estimated Study Completion Date : October 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Anakinra

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 Name: 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 Name: 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 Name: Kineret




Primary Outcome Measures :
  1. Decrease of pro-inflammatory cytokines in brain extracellular fluid (ECF) [ Time Frame: First 48 hours ]
    Decrease of Tumor necrosis factor alpha and interferon gamma cytokines in brain ECF


Secondary Outcome Measures :
  1. Patient outcome GOSe [ Time Frame: 6 months and 12 months ]
    Extended Glasgow Outcome Score (GOSe) assessments at 6 months and 1 year.

  2. Patient outcome SF36 [ Time Frame: 6 months and 12 months ]
    Short Form - 36 (SF-36) assessments at 6 months and 1 year.

  3. Imaging outcome - PET-MRI [ Time Frame: During the first 14 days ]
    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.

  4. Imaging outcome - DTI-MRI [ Time Frame: During the first 14 days ]
    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).

  5. Biochemical outcome - S100B [ Time Frame: During the first 7 days + at 6 months and 12 months ]
    Concentrations of protein biomarkers of tissue fate, S100B in serum (µg/L) twice per day as well as after 6 months and 12 months.

  6. Biochemical outcome - NF-L [ Time Frame: During the first 7 days ]
    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.

  7. Biochemical outcome - Tau [ Time Frame: During the first 7 days ]
    Concentrations of protein biomarkers of tissue fate, microtubuli associated protein tau (tau) measured in microdialysis every 6 hours.

  8. Biochemical outcome - APP [ Time Frame: During the first 7 days ]
    Concentrations of protein biomarkers of tissue fate, Amyloid Precursor Protein Beta (APP) associated protein tau measured in microdialysis every 6 hours.

  9. Biochemical outcome - Autoreactivity versus MBP [ Time Frame: During the first 7 days + at 6 months and 12 months ]
    Concentration of circulating T-cells with autoreactivity towards myelin basic protein (MBP) in serum.

  10. Monitoring outcome - ICP [ Time Frame: First 7 days ]
    Intracranial pressure (ICP, mmHg) during the neuro-critical care unit (NCCU) stay.

  11. Monitoring outcome - CPP [ Time Frame: First 7 days ]
    Cerebral perfusion pressure (CPP, mmHg) during the NCCU stay.

  12. Monitoring outcome - Cerebral Metabolism LPR [ Time Frame: First 7 days ]
    Cerebral metabolism, by measuring lactate:pyruvate ratio (LPR) in microdialysis.

  13. Monitoring outcome - Brain tissue oxygenation [ Time Frame: First 7 days ]
    Brain tissue oxygen (mmHg).

  14. Monitoring outcome - PRx [ Time Frame: First 7 days ]
    Derived variables of cerebral elastance (Pressure reactivity index, PRx).

  15. Pharmacological outcome - Concentration of IL1ra in brain tissue [ Time Frame: First week ]
    IL-1ra brain concentration (pg/ml), measured every 6 hours by cerebral microdialysis.

  16. Pharmacological outcome - Concentration of IL1ra in serum [ Time Frame: First week ]
    IL-1ra serum concentration (pg/ml), measured every 12 hours.

  17. Side effects of the IL1ra [ Time Frame: First week + up to 12 months follow-up ]
    To study any potential side-effect of the drug, both known and unknown.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02997371


Contacts
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Contact: Adel Helmy, MA, MB BChir, FRCS, PhD 00441223 216147 adelhelmy@cantab.net
Contact: Eric P Thelin, MD, PhD 0046739365450 thelin.eric@gmail.com

Locations
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United Kingdom
Cambridge University Hospital NHS Trust
Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
Sponsors and Collaborators
Adel Helmy
Cambridge University Hospitals NHS Foundation Trust
Investigators
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Principal Investigator: Adel Helmy, MA, MB BChir, FRCS, PhD University of Cambridge
Publications:

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Responsible Party: Adel Helmy, MA, MB BChir, PhD, FRCS (SN), University of Cambridge
ClinicalTrials.gov Identifier: NCT02997371    
Other Study ID Numbers: CCTU0185
First Posted: December 20, 2016    Key Record Dates
Last Update Posted: May 8, 2017
Last Verified: May 2017

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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
Keywords provided by Adel Helmy, University of Cambridge:
Traumatic brain injury
Microdialysis
Interleukin-1 receptor antagonist
Magnetic Resonance Imaging
Positron Emission Tomography
Additional relevant MeSH terms:
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Brain Injuries
Brain Injuries, Traumatic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Wounds and Injuries
Interleukin 1 Receptor Antagonist Protein
Antirheumatic Agents