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RESEARCH ARTICLE
The effects of GSK2981710, a medium‐chain triglyceride, on
cognitive function in healthy older participants: A randomised,
placebo‐controlled study
Barry V. O'Neill
1,2
*|Chris M. Dodds
3
*|Sam R. Miller
4
*|Ashutosh Gupta
5
*|
Philip Lawrence
6
*|Jonathan Bullman
7
|Chao Chen
8
|Odile Dewit
6
*|Subramanya Kumar
6
|
Mushi Dustagheer
6
*|Jeffrey Price
6
|Shaila Shabbir
9
|Pradeep J. Nathan
10,11,12
1
GSK Nutrition, GSK Consumer Healthcare,
Brentford, UK
2
Respiratory Health, GSK Consumer
Healthcare, Nyon, Switzerland
3
Department of Psychology, University of
Exeter, Exeter, UK
4
Department of Quantitative Sciences,
GlaxoSmithKline, Stevenage, UK
5
Department of Quantitative Sciences India,
GlaxoSmithKline, Bangalore, India
6
Clinical Unit, GlaxoSmithKline, Cambridge,
UK
7
Clinical Pharmacology Modelling and
Simulation, GlaxoSmithKline, Stevenage, UK
8
Clinical Pharmacology Modelling and
Simulation, GlaxoSmithKline, London, UK
9
Clinical Pharmacology Study Sciences and
Operations, GlaxoSmithKline, Stevenage, UK
10
Sosei Heptares, Cambridge, UK
11
The School of Psychological Sciences,
Monash University, Clayton, Australia
12
Department of Psychiatry, University of
Cambridge, Cambridge, UK
Correspondence
Barry V. O'Neill, Respiratory Health, GSK
Consumer Healthcare, Site Nyon, Route de
l'Etraz 2, Case Postale 1279, CH‐1260, Nyon,
Switzerland.
Email: oneillbar@gmail.com
Funding information
GlaxoSmithKline, Grant/Award Number:
EMI116713
Abstract
Objective: This double‐blind, randomised, placebo‐controlled, two‐part study
assessed the impact of GSK2981710, a medium‐chain triglyceride (MCT) that
liberates ketone bodies, on cognitive function, safety, and tolerability in healthy older
adults.
Methods: Part 1 was a four‐period dose‐selection study (n= 8 complete). Part 2
was a two‐period crossover study (n= 80 complete) assessing the acute (Day 1)
and prolonged (Day 15) effects of GSK2981710 on cognition and memory‐related
neuronal activity. Safety and tolerability of MCT supplementation were monitored
in both parts of the study.
Results: The most common adverse event was diarrhoea (100% and 75% of
participants in Parts 1 and 2, respectively). Most adverse events were mild to
moderate, and 11% participants were withdrawn due to one or more adverse
events. Although GSK2981710 (30 g/day) resulted in increased peak plasma
β‐hydroxybutyrate (BHB) concentrations, no significant improvements in cognitive
function or memory‐related neuronal activity were observed.
Conclusion: Over a duration of 14 days, increasing plasma BHB levels with
daily administration of GSK2981710 had no effects on neuronal activity or
cognitive function. This result indicates that modulating plasma ketone levels with
GSK2981710 may be ineffective in improving cognitive function in healthy older
adults, or the lack of observed effect could be related to several factors including
study population, plasma BHB concentrations, MCT composition, or treatment
duration.
KEYWORDS
ageing, cognition, energy metabolism, ketone, medium‐chain triglyceride
*Barry V. O'Neill, Chris M. Dodds, Sam R. Miller, Ashutosh Gupta, Philip Lawrence, Odile Dewit, and Mushi Dustagheer ‐affiliation at time of study.
Received: 12 October 2018 Revised: 7 March 2019 Accepted: 13 March 2019
DOI: 10.1002/hup.2694
Hum Psychopharmacol Clin Exp. 2019;34:e2694.
https://doi.org/10.1002/hup.2694
© 2019 John Wiley & Sons, Ltd.wileyonlinelibrary.com/journal/hup 1of14
1|INTRODUCTION
Age‐related cognitive impairment describes cognitive decline occur-
ring in healthy individuals with advancing age. With increasing age,
capacity to acquire and retrieve new memories deteriorates, and pro-
cessing speeds slows (Salthouse, 1991; Small, Stern, Tang, & Mayeux,
1999). Although recognised as part of the normal ageing process,
some individuals display greater cognitive decline than would be
expected based on their age and educational background that may
be linked to early stages of Alzheimer's disease (AD), including preclin-
ical AD or mild cognitive impairment (MCI; Lim et al., 2013; Lim et al.,
2014; Lim et al., 2014). MCI can be classified as a transitional state
between normal cognitive function and the neuropathological condi-
tion of AD, which confers increased risk of developing AD (Petersen,
2004; Winblad et al., 2004). Cognitive function impairment is a
common feature of normal ageing, MCI and AD that encompasses
multiple domains, including episodic memory (Blackwell et al., 2004;
Doraiswamy et al., 2012; Egerhazi, Berecz, Bartok, & Degrell, 2007;
Fowler, Saling, Conway, Semple, & Louis, 2002; Lim et al., 2015;
Mormino et al., 2014; Spencer & Raz, 1995; Swainson et al., 2001).
There may also be overlap between mechanisms that cause abnormal
age‐related cognitive impairment, MCI and AD. For example, high
levels of amyloid‐β(Aβ) are associated with greater decline in memory
and working memory in healthy older adults, as well as patients with
MCI and mild‐to‐moderate AD (Doraiswamy et al., 2012; Lim et al.,
2015; Mormino et al., 2014).
The brain is highly metabolically active, relying primarily on glucose
as an energy source (Costantini, Barr, Vogel, & Henderson, 2008). Evi-
dence suggests that impaired glucose metabolism may lead to cogni-
tive impairment in healthy ageing, MCI and AD (Daulatazai, 2017).
For example, cerebral glucose metabolism has been shown to decline
with increasing age, which may predict MCI (Bentourkia et al., 2000;
de Leon et al., 2001). Decreased cerebral glucose metabolism has been
observed in patients with MCI and AD as well as healthy older individ-
uals in a network of areas including the hippocampus, parietal, poste-
rior cingulate, temporal, and frontal cortical regions (Herholz et al.,
2002; Mosconi et al., 2008). Decreased metabolism has also been
shown to correlate with cognitive impairment and cognitive decline
(de Leon et al., 2001; Haxby et al., 1990; Shokouhi et al., 2013;
Mosconi et al., 2008; Landau et al., 2011). The mechanism underlying
this hypometabolism is not yet fully characterised but may be
secondary to amyloid levels, calcium homeostasis dysregulation,
mitochondrial dysfunction, and oxidative damage leading to neurode-
generation (Gu, Huang, & Jiang, 2012; Cabezas‐Opazo et al., 2015;
Angelova & Abramov, 2017). Consequently, it has been suggested
that therapies aimed at correcting impaired glucose metabolism may
be beneficial in treatment of age‐related cognitive impairment, MCI
and AD (Costantini et al., 2008; Cunnane et al., 2016).
One therapeutic approach is the induction of ketosis, causing the
liver to metabolise fatty acids to generate ketone bodies that can pro-
vide an alternative energy source for the brain (Henderson, 2008).
Indeed, ketone bodies have been established as a metabolic pheno-
type characteristic of the AD brain in clinical and preclinical studies
(Ding, Yao, Rettberg, Chen, & Brinton, 2013; Yao et al., 2009). The pri-
mary ketone body generated by the liver is β‐hydroxybutyrate (BHB),
which is taken up by neurones and converted in mitochondria to
acetoacetate, which is oxidised via the tricarboxylic acid cycle to liber-
ate energy (Henderson, 2008). In vitro evidence suggests that BHB
preserves neuronal integrity and stability during glucose deprivation
in rat hippocampal slices (Kashiwaya et al., 2000). A study in healthy
participants with insulin‐induced hypoglycaemia showed that BHB
infusion provides an alternative energy source for the brain and pro-
tects against cognitive dysfunction (Veneman, Mitrakou, Mokan,
Cryer, & Gerich, 1994).
Ketone bodies may be generated by administration of medium‐
chain triglycerides (MCTs), which liberate ketone bodies without die-
tary modification (Cunnane et al., 2016; Henderson, 2008). Indeed, a
robust dose response exists between single‐dose oral MCT administra-
tion and maximal BHB plasma levels with increasing oral MCT doses
(range 10–70 g) resulting in increased plasma BHB (range 0.2–
0.9 mM; see Figure 6 in Cunnane et al., 2016, for details). Alongside this
increase in ketones, cognitive improvements have also been reported
in response to MCT treatment in patients with MCI or AD following a
single dose (Henderson et al., 2009) and after 45 or 90 days of treat-
ment, with improvements primarily in apolipoprotein E4 (APOE4) non-
carriers (Henderson et al., 2009; Reger et al., 2004). Although these
findings are encouraging, there have also been contrasting findings
reported, with limited effects on cognitive function in patients with
AD (Ohnuma et al., 2016), though MCT supplementation was well tol-
erated. Further studies exploring different durations of MCT treatment
with larger sample sizes are warranted, to evaluate potential therapeu-
tic benefit of MCT treatment in patients with MCI or AD. In addition,
very little is known regarding potential cognitive benefits of MCT treat-
ment for individuals with cognitive impairment due to the normal age-
ing process. Given the data related to brain energy metabolism
discussed above, it is fair to assume that the healthy older brain may
present with decreased glucose metabolism (Herholz et al., 2002;
Mosconi et al., 2008). Indeed, recent studies have demonstrated this
to be the case where cognitively healthy older individuals presented
with reduced global brain glucose uptake when compared with a
younger control group (Nugent et al., 2014; Nugent et al., 2016).
Alongside this aberrant glucose metabolism, no differences in brain
ketone metabolism has been reported in older subjects (Croteau,
Castellano, Fortier, et al., 2018). Strikingly, brain ketone metabolism
demonstrated no significant differences between healthy young
adults, older adults, and those with MCI/AD (Nugent et al., 2014,
Castellano et al., 2015, Croteau, Castellano, Richard, et al., 2018).
This finding suggests that although glucose metabolism may be
compromised, ketone metabolism is preserved and the healthy ageing
brain may benefit from MCT supplementation.
This study evaluated potential pro‐cognitive effects of GSK2981710,
an MCT formulation comprising55% 1,2,3‐tricapyrloylglycerol (8‐carbon
chain [C8] fatty acid) and 45% 1,2,3‐tricaprinoylglycerol (10‐carbon
chain [C10] fatty acid) with trace amounts of C6 fatty acids, in older
adults. The primary objective of the study was to examine the effects
of GSK2981710 on cognition and brain function, and the secondary
2of14 O'NEILL ET AL.
objectives of the study was to examine the safety and tolerability of
GSK2981710 as well as its effects on plasma BHB levels. The study
was conducted in two parts. Part 1 was conducted to confirm previous
MCT dose related findings applied to the current study product and to
inform the dose level for use in Part 2, based on pharmacokinetic (PK)
analysis of plasma BHB concentrations. In Part 2, the acute (following a
single dose) and prolonged effects (examined at Day 15, 24 hr after the
final dose on Day 14) of GSK2981710 on BHB plasma concentrations,
cognition, and neural function were assessed. Safety and tolerability
were monitored throughout both parts of the study.
2|MATERIALS AND METHODS
2.1 |Study design
This was a two‐part Phase I single‐centre study (clinicaltrials.gov
identifier: NCT01702480, GSK ID: EMI116713) in older adults
(55–80 years of age), conducted in the United Kingdom. Part 1 was
a randomised, placebo‐controlled, double‐blind, four‐period
dose‐escalation study. Part 2 was a randomised, placebo‐controlled,
double‐blind, two‐period crossover study to evaluate the efficacy of
GSK2981710 30 g following a single and repeat dosing (14 days of
treatment). Two participants participated in both study parts. Protocol
amendments are described in Supplementary Appendix B. The study
was approved by National Research Ethics Service Committee
(East of England, Cambridgeshire, and Hertfordshire) and conducted
in accordance with International Council for Harmonisation Good
Clinical Practice and the Declaration of Helsinki 2008.
2.2 |Participants
Males and nonpregnant females aged 55–80 years were eligible for
inclusion in Part 1.
Exclusion criteria (Parts 1 and 2) included restricted or modified
intake of carbohydrates, proteins, fats, or a ketogenic diet; known
learning disability or learning disorder; history of neurological or
psychiatric disorder; history of drug dependence, as measured by the
Mini Neuro‐psychiatric Interview; and history of suicidal behaviour
or ideation, as measured by the Columbia Suicide Severity Rating
Scale (C‐SSRS). Additional inclusion criteria specific to Part 2 were
Wechsler logical memory test (Wechsler, 1987) score below the mean
level of performance of young healthy adults (cut‐off: <24 on
immediate recall or <22 on delayed recall) and an otherwise normal
neuropsychological performance, as determined by a Mini Mental
State Examination Questionnaire score of ≥25 (Bravo & Hebert,
1997). A full list of inclusion and exclusion criteria is presented in
Supplementary Appendix C.
2.3 |Randomisation and blinding
In Part 1, participants were randomised to four sequences (1:1:1:1)
each including four of the following five treatments over a 2‐week
period: GSK2981710 10, 20, 30, 40 g, or placebo (Supplementary
Appendix A: Figure S1a). In Part 2, participants were randomised to
two groups (1:1) to receive daily oral dosing of either placebo or
GSK2981710 30 g for 14 days, starting on Day 1. After a minimum
7‐day washout (after Day 14) participants crossed over and received
the alternate treatment for a further 14 days (Supplementary
Appendix A: Figure S1b). A randomisation schedule was generated
by validated GSK software. Participants, investigators, and project
team staff were not made aware of treatment allocations.
2.4 |Procedures
2.4.1 |Interventions
Study treatment was supplied in powder sachets mixed with
125–250 ml of water, administered in the morning with breakfast.
GSK2981710 and placebo (safflower oil base, with no/negligible
amounts of MCT) were identical in appearance.
2.4.2 |PK endpoints and assessments
In Part 1, the primary endpoint was the plasma BHB concentration
time course, including estimation of the area under the
concentration‐time curve to the last quantified concentration
(AUC
[0–8 hours]
), the maximum observed concentration (C
max
), and the
first time after dosing at which C
max
was observed (t
max
). PK blood
sampling was completed at each dosing session. Plasma samples were
collected predose and at 30‐min intervals for 8 hr after dosing, except
for 5‐hr post dose, when lunch was served. BHB concentrations were
measured using a Stanbio Beta Hydroxybutyrate Liquicolour kit
(Texas, USA, distributed in the UK by Alere), modified to run in
Microtitre plate format with 10‐μl sample volume. In Part 2, trough
(predose) and postdose plasma samples were collected on Day 1,
and a single plasma sample was taken on Day 15, after breakfast.
Plasma samples during both treatment periods were taken immedi-
ately after pharmacodynamic (PD) assessments.
2.4.3 |PD endpoints and assessments (Part 2)
The primary PD endpoint was cognition function, measured using the
Cambridge Neuropsychological Test Automated Battery (CANTAB;
Swainson et al., 2001; Fowler et al., 2002; Egerhazi et al., 2007;
Nathan et al., 2017) and the Source Memory Task (Cooper, Greve, &
Henson, 2017). CANTAB cognitive assessments (adjusted for placebo)
included CANTAB paired associates learning (PAL) task, CANTAB ver-
bal recognition memory (VRM) task, CANTAB spatial working memory
(SWM) task, CANTAB rapid visual processing (RVP) task, and CANTAB
reaction time (RTI) task.
CANTAB PAL task
This task assesses visual memory and associative learning. Boxes are
displayed on the screen and are opened in a randomised order; one
or more of them will contain a pattern. The patterns are then
O'NEILL ET AL.3of14
displayed in the middle of the screen, one at a time, and the partici-
pant must touch the box where the pattern was originally located. If
the participant makes a mistake, the boxes are reopened to remind
them of the patterns' locations; this is repeated until the participant
is correct. Primary outcome measure: total errors for six shapes and
eight shapes.
CANTAB VRM task
This task examines immediate and delayed memory of verbal informa-
tion under free recall and choice recognition conditions. Participants
are presented with a list of 12 words presented one at a time and
are asked to produce as many words as possible from the list immedi-
ately, recognise target words from a list of targets and distracters and
following a delay recognise target words from a list of targets and
distracters. Primary outcome measure: number of correct responses
(immediate and delayed recall).
CANTAB SWM task
This task examines ability to retain spatial information and to
manipulate remembered items in working memory. Participants are
presented with a number of squares on screen; participants perform
a search to find blue tokens. When a token is found, the participant
must perform a new search to find the next blue token; however,
the token will never be hidden twice in the same box. This is repeated
until all the blue tokens are found. Primary outcome measure:
between search errors.
CANTAB RVP task
This task measures sustained attention, whereby participants are
required to detect a series of individual digits from 2 to 9 presented
in a pseudo‐random order in the centre of the screen and are
required to respond when a specific target sequence is displayed
(for example, 3‐5‐7). Primary outcome measure: A prime (A′; i.e.
signal detection measure of sensitivity to the target, regardless of
response tendency).
CANTAB RTI task
This task assesses psychomotor speed, whereby participants must
select and hold a button at the bottom of the screen. Circles are
presented above (one for the simple mode, and five for the
five‐choice mode.) In each case, a yellow dot will appear in one of
the circles, and the participant must react as soon as possible,
releasing the button at the bottom of the screen, and selecting the
circle in which the dot appeared. Primary outcome measure: reaction
time (ms).
The outcome variables selected for each CANTAB test was based
on their sensitivity to detect changes in ageing and AD (Egerhazi
et al., 2007; Fowler et al., 2002; Nathan et al., 2017; Swainson et al.,
2001) and the demonstrated sensitivity of the tests and outcome
variables to pharmacological modulation (both acute and chronic
treatment) in both healthy young and older subjects (Elliott et al.,
1997; Yurko‐Mauro et al., 2010) as well as patients with AD
(Kuzmickiene & Kaubrys, 2015).
For the source memory task (Cooper et al., 2017), participants
were asked to recognise previously‐presented items (item memory)
and recall their spatial location (source memory). This task was con-
ducted in two phases, a study phase and a test phase. During the
study phase participants were shown 40 objects, half appearing on
the top of the screen, half on the bottom. During the test phase par-
ticipants were reshown the same 40 objects and 20 unstudied objects.
Participants were asked to indicate whether they recognised the item
(item memory) and identify its original location (source memory);
response speed and accuracy were compared between participants.
Previous research has demonstrated a sensitivity of source memory
to age with different effects observed between younger and older
adults (Spencer & Raz, 1995), as well as healthy controls and amnesic
patients (Shimamura & Squire, 1987).
For the CANTAB VRM, CANTAB RVP, and source memory tasks,
higher values correspond to improved performance, with a positive
difference reflecting an improved performance with GSK2981710.
For the CANTAB PAL (6 and 8 shapes), CANTAB SWM (six and eight
boxes), and CANTAB RTI tasks, lower values correspond to improved
performance, with a negative difference reflecting poorer perfor-
mance with GSK2981710.
Secondary PD endpoints included neural activity measured by
electroencephalography (EEG) and event‐related potential, which
included P300, EEG relative power (at various frequency bands) at
rest, and FN400 during the source memory task. P300 and FN400
are electrophysiological EEG markers relating to directed attention
(the contextual updating of working memory) and familiarity (source
memory), respectively. The P300 (P3a and P3b) was included due to
its correlation with age and changes in AD (Alperin, Mott, Holcomb,
& Daffner, 2014; Juckel et al., 2008; Polich, 1997; Polich, 2007). Rest-
ing state EEG has been associated with ageing and neuropsychological
performance in AD (Babiloni et al., 2007; Babiloni, Vecchio, Bultrini,
Luca Romani, & Rossini, 2006).
During EEG measurements, participants were seated upright with
their eyes open in a sound‐attenuated room and instructed to relax
and avoid facial muscle movements. EEG was recorded using tin
electrodes from 61 scalp sites according to the international 10/20
system. Nose and eye movement was recorded via an electrode
placed above, below, and to the left of the left eye ocular orbit and
the right of the right eye ocular orbit, using the point of the nose as
reference (mastoid electrodes were also fitted) and FZ and FPz as
ground. Data were recorded using Neuro Scan equipment with
SynAmps2TM amplifiers (Neuro Scan Inc., Charlotte, NC, USA).
P300 was assessed by comparing the AUC, amplitude, and latency
of P3a and P3b in response to auditory stimuli of varying frequencies
(1,000 Hz [standard], 2,000 Hz [target], white noise burst [novel]),
with a 100‐ms duration, and an intertrial interval of 1,000–2,000 ms
in 100‐ms steps. Participants were instructed to press “Yes”to high‐
frequency tones and ignore standard and novel tones. Resting state
EEG was assessed by comparing relative power (%) of low (delta
[0.5–4 Hz]/theta [4–7 Hz]/alpha [8–13 Hz]) and high (beta [18–35]/
gamma [30–70 Hz]) frequencies from EEG recordings during 3 min
of having the eyes open and closed. Event‐related potential activity
4of14 O'NEILL ET AL.
during the source memory task was assessed by measuring the FN400
AUC and latency from time‐locked EEG recordings, to compare the
participant's speed of response and accuracy during the source mem-
ory task. A positive difference reflects an improvement with
GSK2981710.
CANTAB, resting EEG, and P300 measurements were carried out
at baseline of each study part (6–8 days before Day 1 of each treat-
ment period), on Day 1 (post dose) of each treatment period to assess
acute effects and on Day 15 (trough assessment approximately 1 day
after the last treatment in both treatment periods) to assess prolonged
effects. The source memory task was conducted at baseline and Day 1
(post dose) but not on Day 15. Participants were familiarised with the
use of the touch screen and cognitive tasks prior to cognitive testing
(at screening) to avoid familiarisation effects.
2.4.4 |PK‐PD
The correlation between systemic exposure of BHB and the CANTAB
domain and source memory assessments on Days 1 and 15 were eval-
uated graphically as a secondary objective in Part 2.
2.4.5 |Safety and tolerability
Key safety outcomes included adverse events (AEs), serious AEs,
disease‐related AEs, clinical laboratory tests, vital signs, and electro-
cardiograms were monitored from the start of study treatment until
the end of follow‐up. AEs were coded using the Medical Dictionary
for Regulatory Activities (MedDRA) coding system. Gastrointestinal
(GI) symptoms and stool quality were assessed using self‐administered
diaries, which were reviewed in the morning before each dose.
Participants rated GI symptoms as mild, moderate, or severe. Stool
consistency and quality were assessed by the Bristol Stool Form Scale
(Lewis & Heaton, 1997). A stool consistency that was 1 (watery) or 2
(loose), with a Bristol Stool Form that was 6 (fluffy pieces with jagged
edges) or 7 (watery, no solid pieces) was recorded as a diarrhoea AE.
2.5 |Statistical analysis
2.5.1 |Sample size
This was an exploratory study not specifically designed for hypothesis‐
testing. No sample‐size calculation was performed for Part 1. Sample‐
size calculations for Part 2 showed that 80 participants completing
both periods would provide 80% power to detect an effect‐size of
0.31 for any PD endpoint, with a 5% two‐sided type I error rate.
2.5.2 |Analysis populations
The intention‐to‐treat population included all participants randomised
and receiving at least one dose of GSK2981710 30 g and was used for
safety reporting. The per‐protocol (PP) population included all partici-
pants who were randomised and received at least one dose of
GSK2981710 30 g, except the participants (or specific data points)
where the measurement was identified prior to unblinding as poten-
tially biased. The PP was the primary population for PD endpoints
because it was expected to have greater sensitivity to detect any sig-
nal in the data. The PK population included participants in the
intention‐to‐treat population for whom at least one PK sample was
obtained and analysed.
Individual and mean plasma BHB concentration‐time data were
plotted and analysed by noncompartmental methods using
WinNonlin® (Version 6.3), using actual sampling times recorded dur-
ing the study. C
max
and t
max
were determined from the plasma
concentration‐time curve. The AUC
[0–8 hours]
was determined using
the linear trapezoidal rule for increasing concentrations and the loga-
rithmic trapezoidal rule for decreasing concentrations. Treatment dif-
ferences were calculated by subtracting the values of C
max
and
AUC
[0–8 hours]
for placebo treatment from those for GSK2981710
treatment. PK parameters were summarised using summary statistics.
Taking into consideration the tolerability of GSK2981710, a plasma
BHB concentration of ≥0.4 mmol/L was used as the threshold for
dose selection from Part 1, based on a previous study using the
MCT AC‐1202 (Henderson et al., 2009). Duration of BHB level eleva-
tion was also considered to accommodate the time required to com-
plete PD assessments (approximately 2 hr) in Part 2. Changes from
baseline in PD endpoints for GSK2981710 were compared with pla-
cebo. A repeated measures analysis of variance mixed‐effects model
was applied fitting the period, day, treatment, and day * treatment
interaction as fixed effects, with participant as a random effect and
day as a repeated effect. When measured, participant‐baseline,
period‐baseline, and the interaction term for period‐baseline * day
were included as continuous covariates. Least squares means and
the mean treatment difference with corresponding 95% confidence
intervals and pvalues were calculated. Plasma BHB concentration ver-
sus CANTAB or source memory assessment scores were explored
graphically.
3|RESULTS
In Part 1, 14 participants were screened for eligibility, nine were
randomised and eight completed the study (Figure 1a). In Part 2, 332
participants were screened, of whom 225 failed, 107 were
randomised, and 80 completed the study (Figure 1b). A summary of
participant disposition, including reasons for screen failure, is pre-
sented in Figure 1a,b. Participants were mostly male, >55 years or
age and White/Caucasian/European (Table 1).
In Part 1, BHB exposure and peak plasma concentration generally
increased with increasing GSK2981710 dose. Plasma BHB concentra-
tions peaked within 1 hr after dosing with 10 or 20 g GSK2981710 or
1–2 hr after dosing with 30 or 40 g GSK2981710 (Table 2), and gen-
erally returned to predose levels within 8 hr after dosing (Figure 2a).
GSK2981710 30 g was selected for use in Part 2, based on a mean
(placebo‐corrected) peak BHB plasma concentration of 0.452 mmol/
L at 1.26 hr after dosing (Table 2). In Part 2, mean plasma BHB con-
centrations for Periods 1 and 2, 1 hr after dosing with GSK2981710
O'NEILL ET AL.5of14
30 g on Day 1, were 0.276 and 0.291 mmol/L, respectively, and 0.058
and 0.064 mmol/L for placebo, respectively (Table 3). On Day 15, for
Periods 1 and 2, the mean BHB plasma concentrations were 0.054 and
0.083 mmol/L for GSK2981710 30 g, respectively, compared with
0.054 and 0.055 mmol/L for placebo (similar to predose levels;
Table 3), respectively. Individual plasma BHB concentration time
profiles for Parts 1 and 2 are illustrated in Figure 2.
There was no significant difference between GSK2981710 30 g
and placebo for CANTAB cognitive tasks (Figure 3) or source memory
tasks (Figure 4).
In general, GSK2981710 was not associated with a significant treat-
ment difference in the AUC, latency and amplitude of P3a and P3b
compared with placebo, although statistical significance was observed
for some comparisons, including P3a AUC at Days 1 (central midline,
right Parietal, Parieto‐Occipital midline) and 15 (Fronto‐Central;
Table S1). Compared with placebo, GSK2981710 30 g was not associ-
ated with any significant changes in the AUC or latency of the FN400
component of the EEG during the source memory task (Table S2).
Generally, GSK2981710 had no effect on low (delta [0.5–4 Hz]/
theta [4–7 Hz]/alpha [8–13 Hz]) and high (beta [18–35]/gamma
[30–70 Hz]) resting EEG activity, compared with placebo, although
some significant differences were observed for the theta frequency
band on Days 1 (Parieto‐Occipital and Temporal) and 15 (Temporal;
Table S3).
FIGURE 1 Participant disposition flow chart for Part 1 (a) and Part 2 (b). BP: blood pressure; CANTAB: Cambridge Neuropsychological Test
Automated Battery; EEG: electroencephalogram; ITT: intention‐to‐treat; PP: per protocol
6of14 O'NEILL ET AL.
PD assessments showed no significant correlation between plasma
BHB concentration and individual CANTAB tests and source memory
task assessment scores (Figure 5).
All participants in Part 1 and 96% of participants in Part 2 reported
at least one AE (listed in Table S4). Most AEs were mild to moderate
intensity, although nine participants reported a total of 24 AEs of
severe intensity. Most AEs were GI‐related, most commonly diarrhoea,
which was reported by all participants in Part 1 and 75% of participants
in Part 2. GI‐related AEs were the only AEs reported as drug‐related in
Part 1 and the AEs most‐commonly reported as drug‐related in Part 2
(Table S5). In Part 1, the proportions of participants who experienced
diarrhoea were 38%, 0%, 50%, 67%, and 83% in the period when they
received placebo, GSK2981710 10, 20, 30, and 40 g, respectively, sug-
gesting a dose‐relation between GSK2981710 and diarrhoea. The
number of participants with other GI‐related AEs or other AEs was
small in all periods, which does not allow to draw conclusions on a
dose‐relation between GSK2981710 and GI‐related AEs that are not
diarrhoea or non‐GI‐related AEs. This information informed the deci-
sion to choose 30 g as the dose of GSK2981710 for Part 2.
No serious AEs, deaths, other significant AEs, or electrocardiogram
abnormalities were reported.
4|DISCUSSION
This study investigated effects of GSK2981710 on cognitive function
and neural activity in healthy older adults. In Part 1, GSK2981710 30 g
resulted in a mean peak plasma BHB concentration consistent with
previous work in the literature demonstrating efficacy of MCT on cog-
nitive function (Henderson et al., 2009). This, combined with tolerabil-
ity findings, led to the selection of a GSK2981710 30 g dose in Part 2.
In Part 2, GSK2981710 30 g treatment had no significant overall
effect on cognitive performance measures despite mean 1 hr postdose
BHB levels (following acute administration on Day 1) above those
required for cognitive improvement in the previous positive study of
AC‐1202 in patients with mild‐to‐moderate AD (Henderson et al.,
2009). Although statistical significance was noted for some EEG mea-
surements at some time points (including P3a AUC), these analyses
were not corrected for multiple testing and were not consistent with
effects seen on amplitude, so these differences were deemed unlikely
related to a robust treatment effect. Almost all participants reported at
least one AE, most commonly diarrhoea. Most AEs were mild or mod-
erate in intensity and commonly reported in both GSK2981710 and
placebo groups, although more withdrawals due to GI‐related AEs
were reported in the GSK2981710 treatment group compared with
placebo. Overall these findings suggest that although GSK2981710
was well tolerated in healthy older adults, the current formulation
and dose tested (over a 14‐day period) were ineffective in improving
cognitive function. The findings imply that modulating plasma ketone
levels with MCTs may not be an effective treatment strategy to com-
pensate for reduced glucose metabolism and thus improve cognitive
function in older adult subjects.
Findings from this study contrast results from previous studies
demonstrating associations between MCT treatment, mild ketosis
(Henderson et al., 2009; Reger et al., 2004), BHB salt infusion (Vene-
man et al., 1994), and improved cognitive function. In patients with
mild‐to‐moderate AD, treatment with the MCT AC‐1202 improved
TABLE 1 Participant demographics for Parts 1 and 2 (ITT
population)
Demographics
Part 1
(N=8)
Part 2
(N= 96)
Age in years, mean (SD) 61.0 (5.63) 65.4 (6.19)
Age range 55–72 55–79
Sex, n(%)
Female: 1 (13) 40 (42)
Male: 7 (88) 56 (58)
BMI, (kg/m
2
) mean (SD) 25.29
(3.02)
24.74
(2.85)
BMI range 22.3–29.0 18.6–30.2
Race, n(%)
White–White/Caucasian/European
Heritage
8 (100) 94 (98)
Asian–Central/South Asian Heritage 1 (1)
Asian–South East Asian Heritage 1 (1)
Note. BMI: body mass index; SD: standard deviation; ITT: intention‐to‐
treat.
TABLE 2 Mean (CVb%) plasma BHB pharmacokinetic parameters from Part 1
Regimen Nt
max
(hours)
Placebo corrected
C
max
(mmol/L)
Placebo corrected
AUC
(0–t)
(hr * mmol/L)
Placebo 8 3.02 (0.00–8.04)
GSK2981710 10 g 6 0.52 (0.51–2.50) 0.119 (36.5) 0.287 (43.6)
GSK2981710 20 g 6 0.52 (0.50–3.01) 0.451 (66.4) 1.110 (61.6)
GSK2981710 30 g 6 1.26 (0.50–3.51) 0.452 (184.5) 1.659 (64.8)
GSK2981710 40 g 6 2.26 (0.50–5.51) 0.588 (78.2) 2.277 (61.4)
Median (range); AUC
[0–t]
: area under the plasma concentration‐time curve to the last quantified concentration; BHB: β‐hydroxybutyrate; C
max
: maximum
observed plasma concentration; CVb: between participant coefficient of variation; t
max
: time to first observation of C
max
.
O'NEILL ET AL.7of14
cognition, measured using the ADAS‐Cog, at plasma BHB levels similar
to those achieved in the current study (Henderson et al., 2009).
Another study in patients with AD or MCI showed a significant corre-
lation between elevated plasma BHB following MCT treatment and
improvements in paragraph recall compared with placebo (Reger
et al., 2004). A study of healthy adults with insulin‐induced
hypoglycaemia, showed infusion of BHB reversed the effects of
hypoglycaemia‐induced cognitive dysfunction (Veneman et al., 1994).
However, in all these studies the effects were observed in a popula-
tion with disease‐related pathology (i.e. amyloid; Reger et al., 2004)
and/or reduced glucose metabolism (Veneman et al., 1994). In this
study, although participants with memory impairment were selected
and hypothesised to have lower glucose metabolism, this was not con-
firmed using imaging techniques such as fluorodeoxyglucose positron
emission tomography. The lack of treatment effect in this study could
be due to participants already having sufficient neuronal metabolism
to perform cognitive tasks optimally.
There are, however, several important methodological consider-
ations. Firstly, previous studies that reported positive cognitive effects
with MCT following both acute (Reger et al., 2004) and chronic admin-
istration (Day 45 and Day 90; Henderson et al., 2009) only observed a
significant treatment effect in APOE4 non‐carriers. However, a similar
open‐label study in Japanese patients with AD reported no effects in
APOE4 negative patients. Additionally, in the previous positive stud-
ies, when all genotypes were examined, MCT administration provided
no consistent and significant cognitive benefits (Henderson et al.,
2009; Reger et al., 2004), consistent with our observations. No geno-
type data were collected in our study, so APOE4‐specific effects could
not be examined. Secondly, negative findings in this study may also be
related to insufficient BHB plasma concentrations following
GSK2981710 administration, indicating that the 30 g dose may not
be optimal. Mean concentrations in the two treatment sessions were
0.276 and 0.291 mmol/L and were below the hypothesised effective
concentration of 0.4 mmol/L. In studies in patients with MCI and
AD, mean plasma levels ranged from 0.36 to 0.39 mmol/L (Henderson
et al., 2009) and 0.43 to 0.68 mmol/L (Reger et al., 2004), suggesting
that positive effects on cognition are more likely to be observed when
concentrations are >0.36 mmol/L. This is supported by findings that
cognitive performance is highly correlated with BHB concentrations,
irrespective of APOE4 genotype (Henderson et al., 2009; Reger
et al., 2004). Thirdly, these differences could relate to optimal concen-
trations of BHB (as discussed above) rather than treatment duration.
The positive effects of MCTs on cognition have been observed after
both acute (Reger et al., 2004) and chronic treatment over a 90‐day
period (Henderson et al., 2009). In the latter study however, the
effects on day 45 and 90 were observed and patients BHB levels were
high following dosing (i.e., testing performed 2‐hr postdose during the
rise in plasma BHB; Henderson et al., 2009). This raises the possibility
that the observed effect may be due to an acute effect following the
dose at day 45 and 90 rather than a chronic effect due to
FIGURE 2 Individual BHB concentration‐time profile, Part 1 (a) and Part 2 (b). In Part 1, plasma BHB concentrations peaked within 2 hr before
returning to predose levels within 8 hr. In Part 2, plasma BHB concentrations at 1‐hr postdose on Day 1 for GSK2981710 30 g were consistent
with Part 1. Plasma BHB concentrations on Day 15 were similar to pre‐dose levels on Day 1. Thicker line: median. BHB: β‐hydroxybutyrate.
TABLE 3 Mean (SD) BHB concentrations (mmol/L) in Part 2
Treatment
Session 1 Session 2
Predose Day 1, 1‐hr postdose Day 15 Predose Day 1, 1‐hr postdose Day 15
Placebo 0.088 (0.055) 0.058 (0.019) 0.054 (0.023) 0.094 (0.078) 0.064 (0.031) 0.055 (0.023)
GSK2981710 30 g 0.087 (0.043) 0.291 (0.175) 0.083 (0.088) 0.080 (0.049) 0.276 (0.178) 0.054 (0.019)
Note. BHB: β‐hydroxybutyrate; SD: standard deviation.
8of14 O'NEILL ET AL.
accumulation of BHB concentrations, given that it would be unlikely
for BHB levels to accumulate as shown in the current study and the
prior study (Henderson et al., 2009). In the current study, participants
received GSK2981710 for only 14 days, and cognitive assessments
were carried out on Days 1 (immediately postdose to investigate acute
effects) and 15 (approximately 24‐hr post final dose [i.e. when BHB
levels have returned to baseline levels] to investigate effects of
prolonged treatment over 14 days). Our findings suggest that even
with 14 days of treatment, there were no prolonged effects when
BHB levels returned to baseline levels. This provide some evidence
to suggest that the positive effect reported in the Henderson et al.
(2009) study may indeed be related to the acute effect following the
Days 45 and 90 doses when BHB levels were rising postdose rather
than an accumulation of BHB levels over 90 days leading to chronic
effect. The latter would be unlikely due to BHB levels returning to
baseline levels within 8 hr.
FIGURE 3 Adjusted mean changes from baseline (95% CI) in CANTAB learning tasks: paired associates learning task* (a), verbal recognition
memory task†(b), spatial working memory task* (c), rapid visual processing task†(d), and reaction time* (e). There was no significant difference
between GSK2981710 30 g and placebo for CANTAB assessments on Days 1 and 15 (pvalues: 0.098–0.983). *Lower values correspond to better
performance; †higher values correspond to better performance. CANTAB: Cambridge Neuropsychological Test Automated Battery; CI: confidence
interval; PAL: paired associates learning; RTI: reaction time; RVP: rapid visual processing; SWM: spatial working memory; VRM: verbal recognition
memory
O'NEILL ET AL.9of14
Finally, MCT effects on cognitive function may be influenced by
C8 to C10 ratio. The MCT used in the AC‐1202 study was composed
mainly of glycerine and caprylic acid (C8:0), with 95% C8: 5%
C10/C6 (Henderson et al., 2009), whereas GSK2981710 contains
more C10:0 fatty acids (55% C8: 45% C10). These differences have
been shown to influence ketone body generation in a preclinical
rhesus monkey model (Tetrick, Greer, & Benevenga, 2010). However,
as the BHB levels observed with 30 g of GSK2981710 were similar
to those observed with AC‐1202, it is unlikely that differences in
the ability to generate ketone bodies between the two formulations
impacted efficacy.
There are numerous limitations, which may have impacted the
study. Firstly, the cognitive dysfunction of the study population may
have been too heterogeneous and/or mild at baseline to observe a
consistent treatment effect. Positive findings were reported in
patients with greater cognitive impairment at baseline (and potentially
greater abnormality in glucose metabolism), potentially contributing to
the procognitive benefit. Secondly, although we hypothesised that
healthy older adults enrolled in this study would have abnormal glu-
cose metabolism, this was not confirmed using fluorodeoxyglucose
positron emission tomography imaging. It is possible that not all partic-
ipants had abnormal glucose metabolism, would require an alternative
neuronal energy source, and would gain benefit from GSK2981710.
Although the previous MCT studies discussed (Henderson et al.,
2009; Reger et al., 2004) did not confirm reduced glucose metabolism
either, the inclusion of patients with MCI or AD with disease‐related
pathology suggests that these patients had greater glucose metabo-
lism abnormalities compared with this study. In addition, the samples
administered in this study consisted of MCT and other excipient ingre-
dients including maltodextrin. Previous research has reported and
impaired ketogenesis with increased insulin (Elkeles, Wu, & Hambley,
1978). As such, maltodextrin levels in samples administered in the cur-
rent study may have led to increased insulin, an associated negative
impact on ketone production thereby influencing the reported results.
Finally, cognitive assessments on Day 1 were conducted after break-
fast, when MCT efficacy may have been blunted by subsequent glu-
cose surges. Previous studies that demonstrated efficacy
administered treatment either after an overnight fast, when blood glu-
cose levels were likely low (Reger et al., 2004), or during/after break-
fast, similar to the present study (Henderson et al., 2009). Therefore, it
is unclear whether the variations in efficacy are due to food intake.
Although meal components may have affected MCT absorption and
bioavailability (Bushra, Aslam, & Khan, 2011), this is unlikely as
postdose ketone levels were measured under similar conditions in
Parts 1 and 2.
In summary, this study examined the effects of an alternative
energy source on brain activity and cognitive function in a popula-
tion of healthy older adults with presumed abnormalities in glucose
metabolism. Over a duration of 14 days, increasing plasma BHB
levels with daily administration of GSK2981710 30 g had no effects
on any measure of neuronal activity or cognitive function. The lack
of effect on brain activity and cognitive function in this study sug-
gests that modulating plasma ketones with this particular type of
MCT formulation may not be effective in improving cognitive func-
tion in healthy older subjects. However, the observed results may
be related to the study population, plasma BHB concentrations,
MCT composition, and treatment duration. Further studies address-
ing these particular points are warranted to examine the potential
benefit of ketones as a therapeutic strategy for the treatment of
cognitive impairment.
FUNDING
This work was supported by GlaxoSmithKline (GSK study EMI11
6713).
FIGURE 4 Adjusted mean changes (95% CI)
from baseline in source memory task
assessment scores on Day 1*. There was no
significant difference between GSK2981710
30 g and placebo for item memory (p= 0.863)
and source memory (p= 0.805) tasks. *Higher
values correspond to better performance. CI:
confidence interval
10 of 14 O'NEILL ET AL.
ACKNOWLEDGEMENTS
The authors wish to thank the investigators and the subjects who
participated in this study, and Paul O'Regan, PhD, Fishawack Indicia
Ltd, UK, who provided editorial assistance with developing this
manuscript (in the form of writing assistance, including development
of the initial draft from the clinical study report, assembling tables
and figures, collating authors comments, grammatical editing, and
referencing). Editorial support was funded by GSK. The authors would
like to thank the recruitment co‐ordinator Judy Gilbert and research
nurse Elizabeth Redman for all their help with identifying the
participants and collecting the clinical data for this study, respectively.
Anonymised individual participant data and study documents
can be requested for further research from www.clinicalstudydata
request.com.
FIGURE 5 Pharmacokinetic‐pharmacodynamic correlations. PD assessments showed no significant correlation between plasma BHB
concentration and CANTAB and source memory task assessment scores. *Lower values correspond to better performance; †higher values
correspond to better performance. BHB: β‐hydroxybutyrate; CANTAB: Cambridge Neuropsychological Test Automated Battery; PAL: paired
associates learning; PD: postdose; RTI: reaction time; RVP: rapid visual processing; SWM: spatial working memory; VRM: verbal recognition
memory
O'NEILL ET AL.11 of 14
STATEMENT OF INTEREST
SRM, JB, CC, SK, MD, SS, and JP are employees of GlaxoSmithKline
(GSK) and own their own GSK stock. BVO'N, AG, CMD, OD, PL, and
PJN are former employees of GSK. Their role included study concept
and design, funding of participating centres, analysis of data, develop-
ment, and funding of the final report and manuscript. OD and PJN are
current employees of Heptares Therapeutics Ltd.
CONFLICT OF INTEREST
The authors have declared that there is no conflict of interest.
ORCID
Barry V. O'Neill https://orcid.org/0000-0003-2861-0110
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SUPPORTING INFORMATION
Additional supporting information may be found online in the
Supporting Information section at the end of the article.
How to cite this article: O'Neill BV, Dodds CM, Miller SR,
et al. The effects of GSK2981710, a medium‐chain triglyceride,
on cognitive function in healthy older participants: A
randomised, placebo‐controlled study. Hum Psychopharmacol
Clin Exp. 2019;34:e2694. https://doi.org/10.1002/hup.2694
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