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Spectroscopic and Diffusion Weighted Analysis of the Effects of Dexamethasone on High Altitude Cerebral Oedema (HACE) (D4H)

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ClinicalTrials.gov Identifier: NCT03341676
Recruitment Status : Suspended (COVID)
First Posted : November 14, 2017
Last Update Posted : November 24, 2020
Sponsor:
Information provided by (Responsible Party):
University Hospitals Coventry and Warwickshire NHS Trust

Brief Summary:
When the brain detects a drop in oxygen levels in the blood (hypoxia) there is a compensatory increase in blood flow. Acute mountain sickness (AMS) is a cluster of symptoms which commonly occur in those ascending to high altitude and experiencing hypoxia due to increased blood flow and then swelling in the brain. Symptoms include headache, nausea, insomnia and fatigue. The exact mechanisms by which AMS develops remains poorly understood. Dexamethasone has been shown to reduce the risk of developing significant brain swelling in other settings. Therefore we hypothesise that administering low dose Dexamethasone could protect against hypoxia induced cerebral and spinal oedema.

Condition or disease Intervention/treatment Phase
High Altitude Cerebral Edema Drug: Dexamethasone Drug: Placebo Phase 1

Detailed Description:

The exact mechanisms by which AMS develops remains poorly understood. Interestingly, brain and spinal cord swelling due to low oxygen levels can also occur in the period following surgery to treat thoracic and abdominal aortic aneurysms, dangerous swellings of the major blood vessel in the body. Therefore, if we find a therapeutic benefit of receiving a dose of Dexamethasone in a controlled, reversible setting of hypoxia, it is possible that this could be useful in the treatment of post-operative hypoxia as well.

Work with MRI imaging has demonstrated reduced measures of water movement in patients suffering from cerebral or spinal ischaemia, due to swelling. Specific water channels in brain cells (astrocytes) are involved in the movement of water, and Dexamethasone has been shown to reduce expression of these channels in animal models. Dexamethasone already plays a role in lowering pressure in the brain in the setting of brain tumours. Although high doses are typically used in this setting, there is evidence that lower doses may be equally effective, especially in patients with less severe swelling.

Subjects will be consented and randomised in the weeks before the actual study.

Before entering the tent, the following data will be collected:

  • Lake Louise Acute Mountain Sickness self-assessment questionnaire
  • Pulse oximetry
  • Non-invasive cardiac monitoring (ECG)
  • End tidal CO2
  • Venous blood collection (Full blood count, renal function, S100 and GFAP)
  • Finger-prick blood collection (Purines)
  • Magnetic Resonance Angiography

Non-invasive monitoring will continue every 2 hours at the start of the study and around the time of administration of the study drug. They will continue at less frequent intervals throughout the study period. This includes ECG trace and an AMS self-assessment questionnaire.

Venous sampling will be performed on 5 occasions throughout the study. Finger prick sampling will be done at the same time points

Each subject will have 5 MRI scans during the course of the study.

Subjects will be begin hypoxication 1 hour after entering the tent. They will be returned to normal oxygen levels after 24 hours.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Double-blind, randomised controlled trial
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: The participant, Investigator supervising the visit and the Outcome Assessor will be blinded to the treatment allocation
Primary Purpose: Treatment
Official Title: Spectroscopic and Diffusion Weighted Analysis of the Effects of Dexamethasone on High Altitude Cerebral Oedema (HACE)
Actual Study Start Date : January 14, 2019
Estimated Primary Completion Date : September 4, 2021
Estimated Study Completion Date : September 4, 2021


Arm Intervention/treatment
Experimental: Dexamethasone
8ml IV 3.3mg/mL dexamethasone
Drug: Dexamethasone
Dexamethasone 3.3 mg/mL solution for injection

Placebo Comparator: Placebo
8ml IV 0.9% w/v saline
Drug: Placebo
Sodium Chloride 0.9% w/v solution for injection




Primary Outcome Measures :
  1. Differences in oedematous changes in the brain and spinal cord [ Time Frame: 0 hour and 8, 11, 22 and 26 hours post hypoxic insult ]
    Differences in oedematous changes in the brain and spinal cord as measured by changes in brain and spinal cord MRI imaging


Secondary Outcome Measures :
  1. Primary blood brain barrier breakdown in hypoxic cytotoxic oedema [ Time Frame: 0 hour and 8, 11, 22 and 26 hours post hypoxic insult ]
    To assess the role of primary blood brain barrier breakdown in hypoxic cytotoxic oedema as measured by variation in serum markers

  2. Assessing the usefulness of biomarkers of hypoxic cerebral changes. [ Time Frame: 0 hour and 8, 11, 22 and 26 hours post hypoxic insult ]
    Change in glial specific (GFAP) and non-glial specific (purines) serum biomarkers from baseline and at 8, 11, 22 and 26 hours post hypoxic insult

  3. Spinal cord model [ Time Frame: 0 hour and 8, 11, 22 and 26 hours post hypoxic insult ]
    To develop a hypoxic spinal cord model for use in future research looking into complex vascular surgery.



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Ages Eligible for Study:   20 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Provision of informed consent
  • Healthy men and women aged 20-50 years
  • Ability to fully understand the requirements of the protocol
  • Negative pregnancy
  • BMI <30 kg/m2

Exclusion Criteria:

  • Recent experience of high altitude: Any subject who has visited high altitudes (defined as 8,000 - 12,000 feet above sea level) within 4 weeks of starting the study.
  • Abnormal blood pressure: AHA guidelines state blood pressures ≥140/90 mmHg require medical management. Patients with a blood pressure above these parameters will be excluded.
  • Any evidence of systemic infection e.g. respiratory tract infection.
  • Any evidence of renal disease (i.e. eGFR <60, as this precludes intravenous contrast required for MRI scan)
  • History of Tuberculosis
  • History of heart disease
  • Conditions including but not limited to: Glaucoma (including family history), ocular herpes simplex (risk of corneal perforation), severe affective disorders (particularly if history of steroid-induced psychosis), epilepsy, peptic ulcer, hypothyroidism, history of steroid myopathy, ulcerative colitis, diverticulitis, recent intestinal anastomoses, thromboembolic disorders or myasthenia gravis.
  • Breastfeeding
  • Current smoker
  • Contraindications for MRI
  • Known sensitivity to the study drug and / or it's excipients: History of hypersensitivity to steroids (any preparation).
  • Taking pharmaceutical preparations or over the counter medications known to interact with intravenous Dexamethasone.
  • Current participation in other interventional research

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): NCT03341676


Locations
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United Kingdom
University Hospitals Coventry and Warwickshire NHS Trust
Coventry, West Midlands, United Kingdom, CV2 2DX
Sponsors and Collaborators
University Hospitals Coventry and Warwickshire NHS Trust
Investigators
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Principal Investigator: Christopher Imray, PhD MBBS University Hospital Coventry and Warwickshire NHS Trust
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University Hospitals Coventry and Warwickshire NHS Trust
ClinicalTrials.gov Identifier: NCT03341676    
Other Study ID Numbers: CI175716
First Posted: November 14, 2017    Key Record Dates
Last Update Posted: November 24, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Individual participant data will not be shared with other researchers

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Altitude Sickness
Brain Edema
Edema
Respiration Disorders
Respiratory Tract Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Dexamethasone
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents