Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000548235
Ethics application status
Approved
Date submitted
29/03/2018
Date registered
12/04/2018
Date last updated
14/09/2022
Date data sharing statement initially provided
14/09/2022
Date results information initially provided
14/09/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
Relationships between kidney function and acute mountain sickness symptoms in healthy human adults.
Scientific title
Renal bicarbonate handling in acute mountain sickness in healthy human adults.
Secondary ID [1] 294470 0
Wellington Medical Research Foundation - 114205.01.P.RH
Secondary ID [2] 294487 0
Maurice & Phyllis Paykel Trust - IN210862
Universal Trial Number (UTN)
U111111804145
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute mountain sickness 307232 0
Altitude sickness 307255 0
Condition category
Condition code
Neurological 306345 306345 0 0
Other neurological disorders
Respiratory 306374 306374 0 0
Other respiratory disorders / diseases
Renal and Urogenital 306375 306375 0 0
Normal development and function of male and female renal and urogenital system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The participants will undergo two 10-hour exposure of the following conditions: 1) sea-level condition (fraction of inspired oxygen at 0.21), and 2) a simulated altitude of 5,000m (fraction of inspired oxygen around 0.12) induced in the Global Energetic and Environmental Simulation Suite (GEnESiS), in the Center for Translational Physiology at University of Otago Wellington, in a randomised, single-blinded crossover design, with one week washout period between the experimental sessions. Kidney function measures will be assessed from urine output and pH during the 10 hour exposure, as well as via blood samples taken from a venous cannula to assess creatinine concentration changes every two hours.

Participants will be versed in the expected effects and risks of the stimulated altitude, both in person at a 2-hour one-on-one orientation session (one week prior to the experimental sessions), and in writing at all stages of recruitment and testing. The effects of the simulated altitude will be monitored from within GEnESiS by Dr. Mickey Fan, who has a history of research in Acute Mountain Sickness since 2007. Participants will also be monitored by a clinician at all times.

Over the course of the 10 hour experimental session, participants will mostly be resting in a semi-recumbent position. They will be free to stand up and walk around the chamber in between measurements.
Intervention code [1] 300763 0
Early detection / Screening
Comparator / control treatment
A single 10-hour exposure to sea-level (control) altitude in GEnESiS.
Control group
Active

Outcomes
Primary outcome [1] 305356 0
Acute Mountain Sickness score, as determined by the Lake Louise Questionnaire (LLQ)
Timepoint [1] 305356 0
Prior to entering the chamber, and at two, four, six, eight, and ten hours into the study (LLQ)
Primary outcome [2] 305357 0
Indices of kidney function using a combination of urine output volume, urine pH, and venous blood creatinine concentration.
Timepoint [2] 305357 0
Blood creatinine concentration will be assess upon entering the chamber, and at two, four, six, eight, and ten hours into the study. Urine analysis will occur following the participant's voluntary urination.
Primary outcome [3] 305358 0
Cerebral blood flow dynamics using near-infrared spectroscopy, and Doppler ultrasound.
Timepoint [3] 305358 0
A plethora of ultrasound and spectroscopy based analyses will occur prior to the start of the study, half an hour, two hours, two and a half hours, four hours, four and a half hours, six hours, eight hours, eight and a half hours, and ten hours into the study.
Secondary outcome [1] 344945 0
Safety, as assessed by vital sign monitoring of resting heart rate (ECG) and peripheral oxygen saturation (pulse oximetry) using equivital sensor belt.
Timepoint [1] 344945 0
Continuously within each exposure.
Secondary outcome [2] 344946 0
Body composition/Anthropometry measurements using Dual-energy X-ray absorptiometry
Timepoint [2] 344946 0
Once, at the two-hour orientation session before any exposures have occurred.
Secondary outcome [3] 344947 0
Safety as assess by ventilation using spirometry and expired respiratory gases (partial pressure of end-tidal CO2 & O2) using gas analyzers.
Timepoint [3] 344947 0
At half an hour, two and a half hours, four and a half hours, and eight and a half hours into the study.

Eligibility
Key inclusion criteria
Healthy individuals; aged 18-45 years; free from a history of long-term disease; and not currently taking any medications that could influence the measures in the study (diuretics, antacids, proton pump inhibitors, or histamine blockers).
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Anyone who has been over 2,500m in the two months prior to testing; pregnancy; respiratory or cardiovascular diseases; specific renal impairment; currently taking diuretics, antacids, proton pump inhibitors, or histamine blockers; or a body mass index greater than 30 kg/m2. Exposure cessation criteria are an AMS score above 9 as determined by the LLQ, a resting heart rate above 140 bpm, a peripheral O2 saturation below 65%, subject intolerance or request, or mental abnormalities as assessed by a clinician (i.e.: confusion, incoordination of motor skills).

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central random allocation using a computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a computerised sequence generation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The primary independent variables are AMS Scores, biomarkers of kidney function, and cerebral blood flow dynamics measures.
The key independent factors are condition - the simulated altitude of 5,000m or sea-level control - and the duration of exposure, as the participant may not make it to the end of the proposed 10-hour study.
It has previously been reported that around 80% of individuals develop AMS following acute exposure to ~5,000m altitude, with around 50% developing moderate symptoms. A sample of 30 participants will provide over 80% power to detect an effect size that corresponds to over 50% of the participants developing AMS, assuming a standard deviation of 3 points across AMS scores, at a two-tailed significance of 0.05.
Sex will be controlled for as a potentially confounding factor.
Differences and interactions between experimental conditions and exposure duration will be parsimoniously assessed using generalised mixed-effects models.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
2/03/2018
Date of last participant enrolment
Anticipated
1/11/2018
Actual
1/11/2018
Date of last data collection
Anticipated
30/11/2018
Actual
30/11/2018
Sample size
Target
30
Accrual to date
Final
30
Recruitment outside Australia
Country [1] 10246 0
New Zealand
State/province [1] 10246 0
Wellington Region

Funding & Sponsors
Funding source category [1] 299092 0
Charities/Societies/Foundations
Name [1] 299092 0
Wellington Medical Research Foundation
Country [1] 299092 0
New Zealand
Funding source category [2] 299093 0
University
Name [2] 299093 0
University of Otago Wellington
Country [2] 299093 0
New Zealand
Funding source category [3] 299094 0
Charities/Societies/Foundations
Name [3] 299094 0
Maurice & Phyllis Paykal Trust
Country [3] 299094 0
New Zealand
Primary sponsor type
Individual
Name
Dr Jui Lin Fan
Address
University of Otago Wellington
23a Mein Street
Newtown
Wellington, 6021
New Zealand
Country
New Zealand
Secondary sponsor category [1] 298343 0
University
Name [1] 298343 0
University of Otago Wellington
Address [1] 298343 0
23a Mein Street, Newtown, Wellington, 6021, New Zealand
Country [1] 298343 0
New Zealand
Other collaborator category [1] 280046 0
University
Name [1] 280046 0
Massey University
Address [1] 280046 0
Private Bag 11 222
Palmerston North, 4442, New Zealand
Country [1] 280046 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300029 0
Health & Disability Ethics Committee
Ethics committee address [1] 300029 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 300029 0
New Zealand
Date submitted for ethics approval [1] 300029 0
08/09/2016
Approval date [1] 300029 0
17/10/2016
Ethics approval number [1] 300029 0
16/NTA/153

Summary
Brief summary
Upon rapid ascent to high altitude, increases in breathing can induce respiratory alkalosis - an increase in blood pH. Rapid ascent is known to induce alveolar hyperventilation, where one exhales more than one inhales, increasing the ratio of expelled CO2 to O2 intake. This reduction of CO2 in the blood creates a proportional surplus of bicarbonate ions, and shifts plasma pH to more alkaline levels. In order to restore blood acid-base balance, kidneys must compensate to excrete surplus bicarbonate ions via the urine.
There is evidence of correlation between urine acidity - or lack of bicarbonate clearance - and AMS symptom severity. Furthermore, Acetezolamide, a drug known to improve kidney function at high altitude, is effective at alleviating AMS. Increased blood pH is known to impair cerebral auto-regulation, increase cerebral blood flow, and degrade the blood-brain-barrier. Given the symptoms of AMS, such as dizziness, headaches, nausea, and fatigue/lassitude, and its risks, such as high-altitude cerebral oedema (brain swelling), these changes in cerebral vasculature are a logically assumed source. All this considered, it has been suggested that interpersonal differences in AMS susceptibility arise from differences in kidney function.
This study aims to prove the hypothesis that kidney function, cerebral auto-regulation, and AMS symptom severity are correlated phenomena. We also hope to produce a means of extrapolating AMS risk from measures of kidney function. This will allow future identification of at-risk individuals, and even indicate an avenue of inquiry into the management of AMS. In the advent of advanced transportation, and in the face of severe medical risks and even fatality from untreated AMS, this is pertinent. The study may also provide general information on cardiovascular function and cerebral auto-regulation dynamics within whole-body integrated physiology.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 2552 2552 0 0
/AnzctrAttachments/374814-HDEC Letter 16NTA153_Approved EXP Application.pdf (Ethics approval)
Attachments [2] 2553 2553 0 0
/AnzctrAttachments/374814-AMS Study protocol amended.docx (Protocol)
Attachments [3] 2554 2554 0 0
/AnzctrAttachments/374814-AMS participant information sheet.docx (Participant information/consent)
Attachments [4] 2555 2555 0 0
/AnzctrAttachments/374814-Study Timeline.docx (Supplementary information)
Attachments [5] 2556 2556 0 0
/AnzctrAttachments/374814-DXA scan client questionnaire.docx (Supplementary information)
Attachments [6] 2557 2557 0 0
/AnzctrAttachments/374814-Lake Louise Acute Mountain Sickness Questionnaire.docx (Supplementary information)
Attachments [7] 2558 2558 0 0
/AnzctrAttachments/374814-Environmental symptoms questionnaire.docx (Supplementary information)
Attachments [8] 2559 2559 0 0
/AnzctrAttachments/374814-Mickey Curriculum Vitae.docx (Supplementary information)
Attachments [9] 2560 2560 0 0
/AnzctrAttachments/374814-CTP Health History Questionnaire copy.docx (Supplementary information)

Contacts
Principal investigator
Name 82314 0
Dr Jui Lin Fan
Address 82314 0
University of Otago Wellington, 23a Mein Street, Newtown, Wellington, 6021, New Zealand.
Country 82314 0
New Zealand
Phone 82314 0
+64212968936
Fax 82314 0
Email 82314 0
[email protected]
Contact person for public queries
Name 82315 0
Jui Lin Fan
Address 82315 0
University of Otago Wellington, 23a Mein Street, Newtown, Wellington, 6021, New Zealand.
Country 82315 0
New Zealand
Phone 82315 0
+64212968936
Fax 82315 0
Email 82315 0
[email protected]
Contact person for scientific queries
Name 82316 0
Jui Lin Fan
Address 82316 0
University of Otago Wellington, 23a Mein Street, Newtown, Wellington, 6021, New Zealand.
Country 82316 0
New Zealand
Phone 82316 0
+64212968936
Fax 82316 0
Email 82316 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified individual data of cerebral perfusion, renal function and acute mountain sickness scores.
When will data be available (start and end dates)?
01/01/2021 to 30/11/2028
Available to whom?
International collaborators
Available for what types of analyses?
Modelling analysis for predicting acute mountain sickness severity.
How or where can data be obtained?
Some of the de-identified data is currently available as supplementary data in the published article in Journal of Experimental Physiology (from 1/1/21).


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
17120Study protocol  [email protected]



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Barclay H, Mukerji S, Kayser B, O’Donnell T, Tzeng... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseRespiratory alkalinization and posterior cerebral artery dilatation predict acute mountain sickness severity during 10 h normobaric hypoxia.2021https://dx.doi.org/10.1113/EP088938
EmbaseAppetite, Hypoxia, and Acute Mountain Sickness: A 10-Hour Normobaric Hypoxic Chamber Study.2023https://dx.doi.org/10.1089/ham.2023.0009
N.B. These documents automatically identified may not have been verified by the study sponsor.