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

Primary Purpose

High Altitude Cerebral Edema

Status
Suspended
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
Dexamethasone
Placebo
Sponsored by
University Hospitals Coventry and Warwickshire NHS Trust
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for High Altitude Cerebral Edema

Eligibility Criteria

20 Years - 50 Years (Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • University Hospitals Coventry and Warwickshire NHS Trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Dexamethasone

Placebo

Arm Description

8ml IV 3.3mg/mL dexamethasone

8ml IV 0.9% w/v saline

Outcomes

Primary Outcome Measures

Differences in oedematous changes in the brain and spinal cord
Differences in oedematous changes in the brain and spinal cord as measured by changes in brain and spinal cord MRI imaging

Secondary Outcome Measures

Primary blood brain barrier breakdown in hypoxic cytotoxic oedema
To assess the role of primary blood brain barrier breakdown in hypoxic cytotoxic oedema as measured by variation in serum markers
Assessing the usefulness of biomarkers of hypoxic cerebral changes.
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
Spinal cord model
To develop a hypoxic spinal cord model for use in future research looking into complex vascular surgery.

Full Information

First Posted
March 9, 2017
Last Updated
July 11, 2022
Sponsor
University Hospitals Coventry and Warwickshire NHS Trust
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1. Study Identification

Unique Protocol Identification Number
NCT03341676
Brief Title
Spectroscopic and Diffusion Weighted Analysis of the Effects of Dexamethasone on High Altitude Cerebral Oedema (HACE)
Acronym
D4H
Official Title
Spectroscopic and Diffusion Weighted Analysis of the Effects of Dexamethasone on High Altitude Cerebral Oedema (HACE)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Suspended
Why Stopped
COVID
Study Start Date
January 14, 2019 (Actual)
Primary Completion Date
March 31, 2023 (Anticipated)
Study Completion Date
March 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospitals Coventry and Warwickshire NHS Trust

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
High Altitude Cerebral Edema

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
Double-blind, randomised controlled trial
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
The participant, Investigator supervising the visit and the Outcome Assessor will be blinded to the treatment allocation
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dexamethasone
Arm Type
Experimental
Arm Description
8ml IV 3.3mg/mL dexamethasone
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
8ml IV 0.9% w/v saline
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Intervention Description
Dexamethasone 3.3 mg/mL solution for injection
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Sodium Chloride 0.9% w/v solution for injection
Primary Outcome Measure Information:
Title
Differences in oedematous changes in the brain and spinal cord
Description
Differences in oedematous changes in the brain and spinal cord as measured by changes in brain and spinal cord MRI imaging
Time Frame
0 hour and 8, 11, 22 and 26 hours post hypoxic insult
Secondary Outcome Measure Information:
Title
Primary blood brain barrier breakdown in hypoxic cytotoxic oedema
Description
To assess the role of primary blood brain barrier breakdown in hypoxic cytotoxic oedema as measured by variation in serum markers
Time Frame
0 hour and 8, 11, 22 and 26 hours post hypoxic insult
Title
Assessing the usefulness of biomarkers of hypoxic cerebral changes.
Description
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
Time Frame
0 hour and 8, 11, 22 and 26 hours post hypoxic insult
Title
Spinal cord model
Description
To develop a hypoxic spinal cord model for use in future research looking into complex vascular surgery.
Time Frame
0 hour and 8, 11, 22 and 26 hours post hypoxic insult

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christopher Imray, PhD MBBS
Organizational Affiliation
University Hospital Coventry and Warwickshire NHS Trust
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospitals Coventry and Warwickshire NHS Trust
City
Coventry
State/Province
West Midlands
ZIP/Postal Code
CV2 2DX
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Individual participant data will not be shared with other researchers
Citations:
PubMed Identifier
31651350
Citation
Fisher O, Benson RA, Wayte S, Kimani PK, Hutchinson C, Imray CHE. Multimodal analysis of the effects of dexamethasone on high-altitude cerebral oedema: protocol for a pilot study. Trials. 2019 Oct 24;20(1):604. doi: 10.1186/s13063-019-3681-0.
Results Reference
derived

Learn more about this trial

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

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