Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001603202
Ethics application status
Approved
Date submitted
18/09/2018
Date registered
27/09/2018
Date last updated
21/06/2021
Date data sharing statement initially provided
21/06/2021
Date results provided
21/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of Brain Blood Flow on Cognition Across Healthy Adulthood
Scientific title
Effect of Cerebral Blood Flow on Cognition Across Healthy Adulthood
Secondary ID [1] 295403 0
None
Universal Trial Number (UTN)
U1111-1216-6720
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Aging 308631 0
Cognitive decline 308633 0
Condition category
Condition code
Neurological 307579 307579 0 0
Studies of the normal brain and nervous system
Cardiovascular 308491 308491 0 0
Normal development and function of the cardiovascular system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
To test whether CBF is a cause of decreased cognition, we will dedifferentiate the age-related differences in CBF between young and old healthy adults using a pharmacological aid (i.e., Indomethacin, a non-steroidal anti-inflammatory drug). The currently-proposed study uses a randomised, single-blind mixed (within and between) design whereby young and older adults will complete cognitive tasks with placebo and Indomethacin treatments. Participants will be asked to attend the laboratory for 1 familiarisation (~1 hour) and 2 testing sessions (~3.5 hours each). The familiarisation session is designed for participants to experience complete instrumentation (i.e., complete equipment set up with all physiological variables measured at semi-recumbent rest for a total of 10 minutes) and practice the cognitive tasks 3 times. Testing sessions will start a minimum of 48 hours after familiarisations. During each testing sessions, and after collection of baseline data, each participant will complete cognitive tasks (measuring reaction time and working memory), and tests of neuro/cerebro-vascular function. Following this, participants will receive two pills; either 1.2 mg/kg of Indomethacin and 50 mg of Simethicone, or a placebo and 50 mg of Simethicone. Simethicone is an anti-flatulence medication that has been used previously to prevent GI upset, a potential side-effect of Indomethacin. These will be administered based on a computer-generated randomised order. Then, after 90 minutes of rest (during which participants are free to work, read, chat, or watch a movie), each participant will undergo a second administration of cognitive and neuro/cerebro-vascular function. A minimum 'wash-out' period of 48 hours will occur between testing sessions.

The principal investigator, Professor Cotter, has undertaken multiple studies examining CBF and cerebrovascular function in young and older adults in relation to acute and chronic stressors. This has included PI on a study examining effects of Indomethacin in maximal exercise and in prolonged exercise in ambient heat stress, as well as being CI on studies examining effects of Indomethacin on renal function, CBF and cerebrovascular function with acute and chronic hypoxia. Along with Professor Cotter, PhD Candidate Leena Shoemaker will be delivering the intervention. Within the last 2 years, Ms. Shoemaker has successfully run 3 independent studies using the same primary outcomes and equipment as this trial. Both investigators are First aid certified and familiar with the health and safety requirements for human research of this caliber.

Intervention code [1] 301711 0
Behaviour
Comparator / control treatment
Participants will ingest a placebo (sugar pill of similar colour, shape, and size) during 1 of the 2 sessions. Experimental protocols and measures will be identical between visits to eliminate any extraneous variability.
Control group
Placebo

Outcomes
Primary outcome [1] 306555 0
Cognition assessed by accuracy-adjusted reaction time (ms).
Timepoint [1] 306555 0
45 minutes before and ~106 min after drug/placebo ingestion.
Primary outcome [2] 306556 0
Cerebral blood flow velocity as assessed by transcranial doppler (cm/s)
Timepoint [2] 306556 0
50 minutes before and 90 minutes after placebo.drug ingestion.
Primary outcome [3] 306557 0
Cerebrovascular reactivity to levels of end-tidal CO2 (cm/s/mmHg) as assessed by transcranial doppler and gas analysis. .
Timepoint [3] 306557 0
10 minutes before and 150 minutes after placebo/drug ingestion.
Secondary outcome [1] 348862 0
Gastrointestinal upset, as assessed with a 7 point Likert scale.
Timepoint [1] 348862 0
45 min and immediately before, and 30, 60, 90, 120 min after placebo/indomethacin ingestion.
Secondary outcome [2] 348863 0
Rageski’s Feeling Scale (-5 to +5) to assess affect (i.e., how they are feeling in that moment)
Timepoint [2] 348863 0
45 min and immediately before, and 30, 60, 90, 120 min after placebo/indomethacin ingestion.
Secondary outcome [3] 348864 0
Cardiovascular variable of blood pressure, as assessed by manual and automatic blood pressures.
Timepoint [3] 348864 0
Continuous monitoring 55 minutes before and 90-225 min after placebo/drug ingestion
Secondary outcome [4] 352201 0
Cognition assessed by score of verbal digit span backward (between 1 and 9). Note: This is a primary outcome. NB: This is a primary outcome.
Timepoint [4] 352201 0
45 minutes before and ~106 min after drug/placebo ingestion.
Secondary outcome [5] 352202 0
Cerebrovascular autoregulation (CA) is the ability of the brain to adapt to changes in blood pressure. CA is assessed during postural induced changes in blood pressure, requiring participants to transition from sitting to standing and vice versa once every 10 s, for a total of 3 min. Cerebral blood flow velocity is measured by use of Transcranial Doppler Ultrasound on the head/temple. Blood pressure is measured continuously using a finger-cuff (Finapres).

NB: This is a primary outcome.
Timepoint [5] 352202 0
20 minutes before and 110 minutes after placebo.drug ingestion.
Secondary outcome [6] 352203 0
Neurovascular coupling (NVC). NVC is the difference in blood flow velocity between the middle and posterior cerebral arteries (as assessed with Transcranial Doppler ultrasound) during visual stimulation (flashing black/white checkerboard). Participants will complete 3-min cycles of 30-s eyes shut and 30-s eyes open to a bright visual stimulus. Mean and peak CBFv will be taken from these 30-s cycles. NB: This is a primary outcome.
Timepoint [6] 352203 0
10 and 26 minutes prior to drug ingestion. 90 and 100 min after drug ingestion.
Secondary outcome [7] 352204 0
Cardiovascular variables (heart rate) as assessed by electrocardiogram. .
Timepoint [7] 352204 0
Continuous monitoring 55 minutes before and 90-225 min after placebo/drug ingestion

Eligibility
Key inclusion criteria
No signs of cognitive impairment and non-smoker.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Currently taking, or required to take any medication listed below:
o Cardiac glycosides
o Aminoglycosides
o Diuretics
o Anticoagulants
o Antihypertensive
o Aspirin
o Non-steroidal anti-inflammatories
o Corticosteroids
Known cardiovascular, cerebrovascular, neurological, metabolic, respiratory, renal, or haematological disease or condition.
Allergic to NSAIDs.

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)
All participants will participate in both control and intervention visits. The order of visits is randomly assigned when the participant blindly picks a letter from a hat which has been previously been randomly assigned "Placebo" or "Indomethacin". The person responsible for assessing participant eligibility will remain unaware until the end of each familiarisation session (when they would have already been approved for study participation and signed consent), when the participant blindly picks their letter.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Due to the novelty of our study design, there are no previous studies to inform a power calculation on the effect of a reduction in cerebral blood flow (CBF) on cognitive performance. However, to inform power calculations the effect sizes were determined on the age-related increase in reaction time, as well as the indomethacin induced reduction in CBF:
1. Based on data from Guiney et al., (2017), an effect size of 1.6 was determined where reaction time was increased 132 ± 35 ms in the older compared to the young. The identical reaction time task is used in this study.
2. Based on data reported in Barnes et al.,( 2011), the minimum effect size of indomethacin on CBF was found in older adults with an effect size of 2.8 (pre-INDO 39 ± 5 cm/s vs. post-INDO 27 ± 3 cm/s).
Therefore, a power analysis (power=0.80) was informed by the smallest effect size (d=1.6). Using a repeated measure ANOVA statistical approach, our analysis revealed a necessary sample size of 14 participants for each of the young and old groups.

This counter-balanced, single-blinded design comparing cognition and CBF in young and older adults will use a 2 way repeated measures analysis of variance with a covariate (ANCOVA) of age. This ANCOVA will therefore compare drug (2 levels; drug vs. placebo) and time (2 levels; pre and post pill administration) for primary outcomes of cognitive, CBF, and CBF reactivity to CO2. Posthoc analysis will then be conducted if statistically allowed.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
16/10/2018
Actual
16/10/2018
Date of last participant enrolment
Anticipated
1/04/2019
Actual
21/01/2019
Date of last data collection
Anticipated
20/04/2019
Actual
4/02/2019
Sample size
Target
28
Accrual to date
Final
28
Recruitment outside Australia
Country [1] 10604 0
New Zealand
State/province [1] 10604 0
Otago

Funding & Sponsors
Funding source category [1] 299991 0
University
Name [1] 299991 0
The School of Physical Education, Sport and Exercise Sciences, University of Otago
Country [1] 299991 0
New Zealand
Primary sponsor type
Individual
Name
Jim Cotter
Address
The School of Physical Education, Sport and Exercise Sciences
University of Otago
55 Union St W
Dunedin 9016
Country
New Zealand
Secondary sponsor category [1] 300224 0
Individual
Name [1] 300224 0
Leena Shoemaker
Address [1] 300224 0
The School of Physical Education, Sport and Exercise Sciences
University of Otago
55 Union St W
Dunedin 9016
Country [1] 300224 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300846 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 300846 0
Ethics committee country [1] 300846 0
New Zealand
Date submitted for ethics approval [1] 300846 0
31/07/2018
Approval date [1] 300846 0
12/09/2018
Ethics approval number [1] 300846 0
18/CEN/142

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 85014 0
Prof Jim Cotter
Address 85014 0
School of Physical Education, Sports and Exercise Sciences
University of Otago
PO Box 56
Dunedin 9056
Country 85014 0
New Zealand
Phone 85014 0
+64 3 479-9109
Fax 85014 0
Email 85014 0
[email protected]
Contact person for public queries
Name 85015 0
Leena Shoemaker
Address 85015 0
School of Physical Education, Sport and Exercise Sciences
55 Union St W
North Dunedin, 9016
Country 85015 0
New Zealand
Phone 85015 0
+64 0273630894
Fax 85015 0
Email 85015 0
[email protected]
Contact person for scientific queries
Name 85016 0
Jim Cotter
Address 85016 0
School of Physical Education, Sports and Exercise Sciences
University of Otago
PO Box 56
Dunedin 9056
Country 85016 0
New Zealand
Phone 85016 0
+64 3 479-9109
Fax 85016 0
Email 85016 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?
Individual anonymous data may be shared upon request of corresponding author for all primary outcomes. Means and variances have been presented for each variable (cognition and cerebrovascular function) within the manuscript. Individual and analyzed data is available at DOI 10.6084/m9.figshare.13239335 .
When will data be available (start and end dates)?
Data is available from the manuscript publication (November 16, 2020). Individual and raw data will be available for 5 years upon reasonable request to the corresponding author (JDC).
Available to whom?
Researchers are able to request individual data for collaborative research or meta-analyses.
Available for what types of analyses?
Collaborative research and meta-analyses.
How or where can data be obtained?
Data is available upon request of the corresponding author, JDC via email at [email protected].


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseIndomethacin markedly blunts cerebral perfusion and reactivity, with little cognitive consequence in healthy young and older adults.2021https://dx.doi.org/10.1113/JP280118
N.B. These documents automatically identified may not have been verified by the study sponsor.