Clinical trial NCT02679235
Conditions: Frontal Lobe Hypometabolism
Sponsor: Université de Sherbrooke
Start date: 2016-04-01; Completion date: 2018-08-08
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
BEAT7-001 is a single group study (supplementation). Using a multi-modal brain imaging portfolio, this study will assess whether brain energy metabolism (glucose and ketones), structure or functional connectivity change in older people with frontal glucose hypometabolism after 28 days on an oral dose of 1 g/kg/day of triheptanoin.

Detailed description:

Arms: arm 1: Participant will undergo POST Triheptanoin suppementation 1g/kg body weight for 28 days (dose gradually increased each week, starting at, 0.25, 0.5, 0.75 and then 1 g) separated in 4 doses (with eah meal and before night) after a control PRE supplementation imaging protocol.
Interventions: intervention 1: POST Triheptanoin
Intervention descriptions: intervention 1: The target daily dose of triheptanoin will be 1 g/kg/d, or approximately 70 g/d during 28±2 days. It will be divided into four daily doses, one of which will be consumed at each meal and one with an evening snack.

Protocol documents:
Prot_SAP_000.pdf: 
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PROTOCOL Amendment 1 
 
Protocol title:  
Brain Energy and Aging with Triheptanoin: The BEAT7 Study 
 
Protocol number:  
BEAT7-001 / 2016-617 
 
Date: November 24, 2015 
 
Amendment 1: April 4, 2017 
 
Principal Investigator: 
Dr. Stephen Cunnane, PhD, Professor, Dept. Medicine, Université de Sherbrooke 
Tel: 819-780-2220, ext. 45670 
 
Clinical co-principal investigator: 
Dr. Tamas Fulop, MD, PhD, Professor, Dept. Medicine, Université de Sherbrooke 
Tel: 819-780-2220, ext. 46212 
 
 
Collaborators: 
Dr. Éric Turcotte, MD, PhD, Professor, Dept. Nuclear Medicine, Université de Sherbrooke 
Dr. Christian Bocti, MD, Professor, Dept. Medicine, Université de Sherbrooke 
Dr. Kevin Whittingstall, PhD, Professor, Dept. Radiology, Université de Sherbrooke 
Dr. Maxime Descoteaux, PhD, Professor, Dept. Computer Science, Université de Sherbrooke 
Dr. Sylvia Stockler, MD, Professor, University of British Columbia 
Sravan Jaggumantri, PhD student, University of British Columbia 
 
Investigational product and support: 
Ultragenyx 
  
 
 
 
 


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Investigator signature page 
 
I agree to implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
 
__________________________ 
 
___________________ 
 
___________ 
Investigator Printed Name  
 
Signature 
 
 
 
Date  
 
 
 
 
__________________________ 
 
___________________ 
 
___________ 
Investigator Printed Name  
 
Signature 
 
 
 
Date  
 
 
 
 


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Table of Contents 
 
1. 
DEFINITIONS AND ABBREVIATIONS .................................................................................. 5 
2. 
BACKGROUND .................................................................................................................... 6 
Overview ............................................................................................................................ 6 
Brain exhaustion in Alzheimer’s disease - cause, consequence or both? ......................... 6 
Brain energy exhaustion in Alzheimer’s disease is specific to glucose .............................. 7 
Ketones, ketogenic diets and ketogenic supplements ...................................................... 8 
Ketogenesis plus anaplerosis – a better way to sustain brain energy supply ................... 9 
Neuroimaging portfolio: linking brain fuel metabolism, structure and functional connectivity
 ............................................................................................................................................ 9 
Rationale .......................................................................................................................... 11 
3. 
PRELIMINARY DATA ......................................................................................................... 11 
Ketogenic diet and dual tracer brain PET ......................................................................... 11 
4. 
STUDY OBJECTIVE ............................................................................................................ 12 
5. 
STUDY HYPOTHESIS ......................................................................................................... 12 
6. 
STUDY DESIGN ................................................................................................................. 12 
Overview .......................................................................................................................... 12 
7. 
SELECTION AND WITHDRAWL OF PARTICIPANTS .......................................................... 12 
7a. Study population ........................................................................................................ 12 
7b. Selection criteria ........................................................................................................ 12 
7c. Participant recruitment and screening ....................................................................... 13 
7d. Intervention ................................................................................................................ 14 
8. 
STUDY DURATION ............................................................................................................ 14 
9. 
RESPONSE MEASURES ..................................................................................................... 14 
9a. Co-primary outcome measures .................................................................................. 14 
9b. Secondary outcome measures ................................................................................... 14 
10. 
STUDY METHODS AND PROCEDURES .............................................................................. 14 
Informed consent ............................................................................................................ 15 
Medical history ................................................................................................................ 15 
Neurological assessment ................................................................................................. 15 
Laboratory assessments .................................................................................................. 15 
Neuroimaging ................................................................................................................... 15 
11. 
SAMPLE SIZE ..................................................................................................................... 16 


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12. 
CONCURRENT THERAPIES ................................................................................................ 16 
Permissible medication .................................................................................................... 16 
Rescue medication ........................................................................................................... 16 
13. 
COMPLIANCE WITH PROTOCOL ....................................................................................... 16 
14. 
STUDY WITHDRAWAL....................................................................................................... 17 
Study withdrawal criteria ................................................................................................. 17 
15. 
STUDY MANAGEMENT ..................................................................................................... 17 
16. 
SAFETY .............................................................................................................................. 17 
Adverse events (AE) ......................................................................................................... 18 
Serious adverse events (SAE) ........................................................................................... 18 
Clinical laboratory abnormalities and other abnormal assessments as AEs and SAEs .... 18 
Time period, frequency, and method of detecting AEs ................................................... 18 
Recording of AEs and SAEs ............................................................................................... 19 
Prompt reporting of SAEs ................................................................................................. 19 
Evaluating AEs and SAEs ................................................................................................... 19 
Follow-up of AEs and SAEs ............................................................................................... 20 
17. 
DATA ANALYSIS ................................................................................................................ 20 
Expected outcomes .......................................................................................................... 20 
Interpretation of results ................................................................................................... 21 
18. 
DATA COLLECTION AND STORAGE ................................................................................... 21 
19. 
REFERENCES ...................................................................................................................... 22 
 
 


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1. DEFINITIONS AND ABBREVIATIONS 
 
Alzheimer’s disease: A clinical syndrome involving a memory disorder and impairment in at least one 
other cognitive domain, both of which significantly interfere with social function or activities of 
daily living.  
Anaplerosis: The process by which citric acid cycle intermediates are replaced by molecules such as 
pyruvate or propionate. Insufficient anaplerosis may contribute to increasing the risk of brain 
energy exhaustion, a problem that can potentially be avoided or diminished with triheptanoin (see 
Triheptanoin below).  
CMR-A (cerebral metabolic rate of acetoacetate): The brain uptake of the ketone, acetoacetate, as 
determined by PET using 11C-acetoactate and expressed as mol/100 g/min. 
CMR-G (cerebral metabolic rate of glucose): The brain uptake of glucose as determined by PET with 
the tracer, 18F-flurodeoxyglucose (FDG), and expressed as mol/100 g/min. 
PET (positron emission tomography): An imaging method we use to quantify brain uptake of ketones 
(11C-acetoacetate) and glucose (FDG). In our PET protocol, the two tracers are injected sequentially 
on the same afternoon so as to necessitate only one visit and so as to minimize biological 
variability between scans obtained on different days.  
Diffusion Magnetic Resonance Imaging: MRI modality involving the reconstruction of white matter 
fiber bundles (tracts) and measures of white matter integrity. 
FDG (18F-flurodeoxyglucose): The PET tracer for tissue glucose uptake studies. 
Investigational product: Triheptanoin (UX-007; Ultragenyx, Novato, CA, USA) 
Ketones: Mainly -hydroxybutyrate and acetoacetate, the four-carbon ‘ketone bodies’ which are the 
key alternative brain fuels to glucose. -Hydroxybutyrate is converted to acetoacetate and then to 
acetyl CoA which enters the citric acid cycle. Our PET ketone tracer is carbon-11 (11C)-acetoacetate. 
Molecules that give rise to ketones are ketogenic, i.e. triheptanoin (see below). 
Mild cognitive impairment: Combination of (i) informant-corroborated memory complaint, (ii) mild 
memory deficit on objective cognitive testing, (iii) normal general cognitive function, (iv) normal 
activities of daily living, and (v) absence of Alzheimer’s disease or dementia. 
Neuroimaging portfolio: Our neuroimaging portfolio combines dual tracer PET (11C-acetoacetate and 
FDG) with diffusion MRI, resting state functional MRI and volumetric MRI. 
REC (Research Ethics Committee of the Research Center on Aging). The committee authorized to 
approve all human research at our institution, and to which all SAEs will be reported.  
Resting state functional magnetic resonance imaging: MRI modality that shows the areas of the brain 
that are synchronized when the subject is at rest, i.e. when not performing a task. 
SAE (Serious adverse event): An SAE is any untoward medical occurrence that, at any dose of the 
investigational product, results in death, is life-threatening, requires hospitalization or 
prolongation of existing hospitalisation, results in disability or incapacity, is a congenital 
abnormality or birth defect, or is a significant medical event. 
Triheptanoin: An edible medium chain triglyceride oil composed of three heptanoic acids (seven 
carbon saturated fatty acids). The potential importance of triheptanoin for brain energy 
metabolism during aging is that it is both ketogenic and anaplerotic. Unlike classical eight- or ten-
carbon medium chain triglycerides, triheptanoin gives rise to both four and five carbon ketones. 
Volumetric MRI: A term referring to the MRI modality that measures cortical thickness, and volume of 
regional grey matter, white matter, ventricles and cerebrospinal fluid surrounding the brain. 
 
 


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2. BACKGROUND 
 
Overview 
Glucose uptake and utilization is significantly lower in the brain of patients with Alzheimer’s 
disease, a situation that progressively leads to brain energy exhaustion. Without sufficient energy for 
brain cells, normal communication between neurons is impaired leading to impaired memory and 
cognitive function. We believe that there is good evidence that brain energy exhaustion not only 
underlies and contributes to the development of Alzheimer’s disease but could be at least partially 
correctable by triheptanoin.  
The novelty of this trial is fourfold: (i) Its rationale is that the core issue leading to Alzheimer’s 
disease is a metabolic (energy) problem with glucose in the brain. Although well-supported by the 
literature, this is still very much an emerging perspective. (ii) Replacing deteriorating brain glucose 
uptake by a dietary supplement that raises ketones has been tested before but has not been 
convincingly shown to improve cognition in Alzheimer’s disease. We are proposing to use 
triheptanoin which should be more effective than classic ketogenic supplements but has not been 
tested in humans to delay declining brain glucose metabolism in older people. (iii) How increased 
availability of ketones affects human brain energy metabolism, structure and function is unknown. 
Our cutting-edge neuroimaging portfolio provides us with a unique capability to examine the effect of 
triheptanoin on brain energy metabolism (glucose and ketones), structure of white matter tracts, and 
functional connectivity across brain regions. Our neuroimaging portfolio is unique because it includes 
a measure of brain ketone uptake, a key capability for this study which only our group has at the 
moment. (iv) We will conduct this study in older people with lower brain glucose uptake. Nothing has 
been done to establish how brain energy metabolism, functional connectivity and/or white matter 
structure may be changing in older people in ways that predispose to Alzheimer’s disease, so this is 
novel.     
 
Brain exhaustion in Alzheimer’s disease - cause, consequence or both? 
Brain function requires a lot of energy, i.e. ~20% of the body’s energy intake goes to the brain 
despite it weighing only ~2% of body weight in adults. For >30 years now, positron emission 
tomography (PET) studies in Alzheimer’s disease have shown that uptake of glucose, the brain’s main 
fuel, is reduced in certain brain regions by 30-40% (reviewed by Silverman et al. 2001; Cunnane et al. 
2011). The brain glucose uptake deficit is predominantly in the parietal cortex, temporal cortex, 
precuneus and posterior cingulate. This specific regional pattern of brain glucose hypometabolism 
helps distinguish Alzheimer’s disease from normal aging and other forms of dementia (Silverman et al. 
2001). With the wide interest in beta-amyloid and plaque accumulation, the general interpretation of 
these studies was and continues to be that brain glucose uptake decreases in Alzheimer’s disease due 
to synaptic deterioration and neuronal dysfunction: thus, as a consequence of needing less glucose, 
brain glucose uptake declines.  
While it is certainly true that brain glucose uptake will decline as a consequence of declining 
neuronal (especially synaptic) function, there are several clear examples of conditions in which lower 
brain glucose uptake is present pre-symptomatically in those at risk of Alzheimer’s disease, i.e. before 
the emergence of any clinically measurable cognitive deficit associated with Alzheimer’s disease. 
These examples include – (i) Presenilin-1 carriers, who are essentially guaranteed to get early onset 
Alzheimer’s disease (Scholl et al. 2011), (ii) Apolipoprotein E4 carriers, who as heterozygotes are at 


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four fold and as homozygotes are at 19 fold higher risk of Alzheimer’s disease (Reiman et al. 2004), 
(iii) Maternal familial history of Alzheimer’s disease (Mosconi et al. 2010), and (iv) Type 2 pre-
diabetics and/or insulin resistance, which are the most important lifestyle risk factors for Alzheimer’s 
disease (Baker et al. 2011; Cunnane et al., unpublished). In the Presenilin-1 carriers, apolipoprotein E4 
carriers, and in those with a maternal family history of Alzheimer’s disease, the lower regional brain 
glucose uptake is present 20-30 years before the expected decline in cognition; in our young women 
with mild insulin resistance, the lower brain glucose uptake is present at 24 years old, i.e. 40 years 
before the typical onset of Alzheimer’s disease (Cunnane et al., unpublished).  
Thus, low brain glucose uptake in moderately 
advanced Alzheimer’s disease is logically in part a 
product of less demand for fuel caused by neuronal 
dysfunction. However, before the clinical onset of 
Alzheimer’s disease symptoms, the examples given 
above show that latent pre-symptomatic brain glucose 
hypometabolism potentially also contributes towards 
cognitive decline (Veech et al. 2004; Henderson et al. 
2009; Cunnane et al. 2011; Mamelak 2012; Castellano 
et al. 2015). We have proposed that latent glucose 
hypometabolism gradually leads towards brain energy 
exhaustion, which could in turn lead to neuronal 
dysfunction, gradual cognitive decline and further 
glucose hypometabolism creating a vicious cycle leading 
to dementia (Cunnane et al. 2011; Castellano et al. 
2015; see Figure on the right).  
 
Brain energy exhaustion in Alzheimer’s disease is specific to glucose  
When glucose supply to the brain is low, ketones (or ketone bodies - beta-hydroxybutyrate and 
acetoacetate) are the only fuels that replace glucose for the brain in a quantitatively important sense. 
This makes the brain unique relative to other organs all of which routinely use fatty acids to replace 
glucose on a daily basis, ex. between meals or during fasting or sleep (Owen et al. 1967; Hasselbalch 
et al. 1996; Maalouf et al. 2009; Cunnane et al. 2011). Ketones access the brain via monocarboxylic 
acid transporters and enter the citric acid cycle at acetyl-CoA, so they generate ATP in the brain 
independently of both glucose uptake and glycolysis.  
The brain has two strategies to acquire its main fuels – a ‘pull’ strategy for glucose and a ‘push’ 
strategy for ketones. The ‘pull’ strategy for glucose refers to the increase in brain glucose uptake that 
is driven by brain cells in response to their activation, i.e. once activated, neurons ‘pull in’ glucose 
from the blood to replace ATP. The ‘push’ strategy for ketones refers to the increase in brain ketone 
uptake that is driven by increased plasma ketones which rise when plasma glucose and insulin 
decrease, i.e. higher blood ketones ‘push’ into the brain when blood glucose is declining. The push 
strategy for ketones is a critical component of our novel solution to delaying Alzheimer’s disease by 
preventing brain energy exhaustion. 
The main PET tracer for brain fuel uptake studies is the glucose analog - 18F-flurodeoxyglucose 
[FDG]). Until we developed carbon-11-acetoacetate (11C-AcAc) to use as a PET ketone tracer (Nugent 
et al. 2014a; Castellano et al. 2015), there was no way to measure brain ketone uptake on a region-


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by-region basis in humans. Being able to compare the brain uptake of glucose and ketones is critical 
to understanding both the nature of the early stage of brain energy exhaustion in older people and 
possible ways to correct or delay it.  
Using our dual tracer PET protocol (injecting 11C-AcAc followed by FDG all within 3 hours on the 
same day), we have recently reported that, as expected, regional brain glucose uptake was about 17% 
lower in mild Alzheimer’s disease. However, brain ketone uptake was not different compared to 
cognitively normal, age-matched controls (Castellano et al. 2015). Our PET results confirm two older 
studies done using arterio-venous difference across the whole brain to measure glucose and ketone 
uptake in Alzheimer’s disease (Lying-Tunell et al. 1981; Ogawa et al. 1996). Collectively, these three 
studies have important implications for developing a strategy to prevent brain energy exhaustion in 
older people because they suggest that brain ketone uptake is still normal even though brain glucose 
uptake is regionally and globally decreased in mild-moderate Alzheimer’s disease. At least early in 
Alzheimer’s disease, it is therefore incorrect to refer to ‘brain hypometabolism’ as a general 
phenomenon because it does not apply to ketones and appears to be specific to glucose. 
 
Ketones, ketogenic diets and ketogenic supplements 
Small clinical trials show that mildly raising blood ketones improves cognitive outcomes in mild 
cognitive impairment or mild-moderate Alzheimer’s disease. This is typically done using a ketogenic 
diet (Krikorian et al. 2012) or a ketogenic supplement providing eight and/or ten carbon ‘classical’ 
medium chain fatty acids (Reger et al. 2004; Henderson et al. 2009). The fact that brain ketone uptake 
is still normal in mild-moderate Alzheimer’s disease (Lying-Tunell et al. 1981; Ogawa et al. 1996; 
Castellano et al. 2015) suggests that the mechanism by which ketones improve cognitive outcomes in 
mild cognitive impairment or Alzheimer’s disease is at least in part by providing the brain with an 
alternative fuel that bypasses the regional brain glucose hypometabolism. This is the physiological 
means by which the brain is fueled during fasting because ketone transport into the brain and their 
access to the citric acid cycle is independent of glucose or the glycolytic pathway. Therefore, with 
ketones as an alternative brain fuel to glucose, the risk of further neuronal dysfunction due to 
progressive brain exhaustion would appear to be reduced.  
As a result, in principle, cognition could be stabilized or possibly even improved. Ketogenic diets 
and supplements have been used clinically to treat intractable epilepsy for decades (Couch et al. 
1999; Neal et al. 2008) and are being explored as treatments in Alzheimer’s disease (Henderson et al. 
2009) and brain cancer (Seyfreid et al. 2014). Ketogenic supplements may be beneficial to counteract 
the symptoms of hypoglycemia in Type 1 diabetics being aggressively treated with insulin (Page et al. 
2009). Some ketogenic supplements are already on the market (Axona®, Betaquik®, Fuel for 
Thought®) and others are undergoing clinical trials.  
To achieve mild nutritional ketosis requires one of the following two strategies: (i) Produce ketones 
from long-chain fatty acids which are 16-18 carbon fatty acids that make up the common dietary fats 
and body fat stores. This strategy requires sustained hypoinsulinemia achieved only by severely 
limiting carbohydrate intake to <5% of total energy intake and increasing fat intake to 80-90% of 
energy. Such a very high fat ‘ketogenic diet’ permits the body to release more long chain fatty acids 
from fat stores and from dietary fat in order to drive ketone production by the liver. However, the 
major constraint is that insulin production must remain low, i.e. carbohydrate intake must be very 
low. (ii) Produce ketones from medium-chain fatty acids (8-12 carbon fatty acids), which involves 
taking a medium chain triglyceride supplement. The big advantage is that this approach avoids the 
dramatic change in macronutrient intake required by a ketogenic diet. Medium chain fatty acids 


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bypass the carnitine-dependent step in fatty acid transport for mitochondrial beta-oxidation and are 
moderately ketogenic. Both strategies safely raise blood ketones but also have their disadvantages: 
ketogenic diets are hard to maintain in adults because the slightest increase in carbohydrate intake 
breaks the ketosis; ketogenic supplements are simpler but have gastrointestinal side-effects.  
 
Ketogenesis plus anaplerosis – a better way to sustain brain energy supply 
One reason that classic ketogenic diets or supplements have only a marginal to modest beneficial 
effect on cognition in older people may be because long-term use of ketogenic diets or ketogenic 
supplements based on even-numbered medium chain fatty acids appears to deplete citric acid 
(Krebs’) cycle intermediates on the way towards producing energy, i.e. ATP (Mochel et al. 2005; 
Brunengraber and Roe 2006; Deng et al. 2009). Molecules in the citric acid cycle such as oxaloacetate 
are intermediates contributing to the cyclical replacement of citric acid but must themselves be 
replaced for the cycle to continue efficiently generating ATP. Replacing the citric acid cycle 
intermediates is a process called anaplerosis. The citric acid cycle is important for energy production 
but it is also needed to make several molecules, including the neurotransmitter, gamma-aminobutyric 
acid.  
When glucose is the main fuel for the brain, it supplies both the carbon to make the ATP and the 
carbon for the intermediates of the citric acid cycle. As an analogy, glucose acts like both the gasoline 
and the motor oil for the engine. However, unlike glucose, the even-carbon numbered ketones 
produced from most ketogenic supplements do not replace citric acid cycle intermediates, i.e. 
ketones provide the gasoline but not the motor oil. This is because virtually all medium- or long-chain 
fatty acids in the diet are ‘even numbered’ i.e. 8, 10, 12, 14, 16, 18, 20 carbons in length, so do not get 
converted to oxaloacetate.  
The process by which carbon to make citric acid cycle intermediates is anaplerosis, while the 
opposite process (the depletion of the intermediates) is cataplerosis (Brunengraber & Roe, 2006). 
Ideally, there is a balance between anaplerosis and cataplerosis but long-term ketogenesis tends to be 
cataplerotic, which curtails the efficacy of both ketone oxidation as an energy substrate and the 
production of neurotransmitters such as gamma-aminobutyric acid which may be part of the 
beneficial effect of ketogenesis (Yudkoff et al. 2005; Roy et al. 2015).    
 
Neuroimaging portfolio: linking brain fuel metabolism, structure and functional connectivity 
Our neuroimaging portfolio integrates dual tracer PET with three magnetic resonance imaging 
(MRI) modalities. We developed this portfolio with the specific goal of measuring how brain metabolic 
vulnerability develops in older people and to find out how metabolic deterioration in the brain affects 
white matter integrity and functional connectivity. Our neuroimaging portfolio consists of four 
modalities:  
(i) Dual tracer brain PET. Our dual tracer brain PET protocol with FDG and 11C-AcAc provides an 
important and unique (at present) window on brain energy metabolism because we quantify uptake 
of both the brain’s main fuels. Our quantification involves measuring the actual metabolic uptake of 
FDG and 11C-AcAc and expressing these data as the cerebral metabolic rate of glucose (CMR-G) and 
11C-AcAc (CMR-A), respectively (Nugent et al. 2014a, 2014b; Castellano et al. 2015). The units for 
CMR-G and CMR-A are mol/100 grams/minute, which combine the rate constants for FDG and 11C-
AcAc uptake with their plasma concentrations. We obtain CMR-G and CMR-A values for the whole 
brain and for multiple brain regions. These values are the only way to know the actual deficit in 


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glucose uptake in a specific brain region and, hence, the therapeutic target for the triheptanoin in the 
present study. The more commonly used statistical parametric mapping procedures greatly simplify 
the estimation of the glucose deficit and mapping it onto the brain. However, they only show a 
statistical difference between brain regions and do not provide a true measure of the quantitative 
difference between regions. Hence, we know the actual deficit in brain glucose uptake and can 
calculate both the therapeutic target and the quantitative effect of triheptanoin on brain fuel uptake.  
Until we developed ketone PET, there was no marker of regional brain ketone metabolism and no 
explanation of how ketogenic diets or supplements would potentially improve cognition. This new 
window on brain fuel metabolism is important because, in rats, our dual tracer brain PET method 
shows the expected increase in brain ketone uptake in response to mild nutritional ketosis, but also 
shows an unexpected increase in brain glucose uptake (Pifferi et al. 2011; Roy et al. 2012). We are in 
the process of confirming this observation in humans on a short-term ketogenic diet (Courchesne-
Loyer et al 2015; see Preliminary Results). Indeed, it would be very interesting if any treatment could 
not only increase brain ketone uptake but also delay or reverse the gradual decline in brain glucose 
uptake.  
(ii) Volumetric MRI. Volumetric MRI (vMRI) refers to the T1-MRI-based measurement of cortical 
thickness and regional gray matter, white matter and cerebrospinal fluid volumes by MRI. We 
compute these volumes for multiple brain regions. Like others, we have shown cortical gray matter 
and sub-cortical structures (hippocampus, thalamus) are 15-25% smaller in early Alzheimer’s disease 
(Nugent et al 2014a, 2014b; Castellano et al 2015). These measurements are in themselves important 
indicators of change associated with aging and risk of cognitive decline. In addition, they are essential 
to correctly measure CMR-G and CMR-A.  
(iii) Diffusion and rsfMRI. We use state-of-the-art fiber tractography that can identify fiber 
crossings (Descoteaux et al. 2009; Girard-Tremblay et al. 2014) and automatic tractography dissection 
to reconstruct the brain’s white matter fiber bundles or tracts. dMRI tractography is therefore a 
powerful tool to dissect the brain’s white matter into its specific structural regions of interest. As a 
result, the integrity of white matter can be assessed both globally and for specific tracts connecting 
regions of the brain that are known to be highly synchronized, such as the default mode network 
which is measured using rsfMRI. Using our PET data, particularly with FDG, we are using the grey 
matter and sub-cortical regions with low FDG uptake in Alzheimer’s disease to study the integrity of 
white matter bundles inter-connecting these regions to establish whether low FDG uptake is 
associated with deteriorating white matter bundles or whether the former is independent of the 
latter. White matter bundles connecting to the thalamus are of particular interest in this respect 
because the thalamus shows low FDG uptake in Alzheimer’s disease (Castellano et al 2015).  
(iv) Dual tracer PET, rsfMRI and neuropathology. The brain’s ‘default mode network’ as measured 
by resting state functional magnetic resonance imaging (rsfMRI) correlates well with the pattern of 
brain amyloid-beta accumulation in Alzheimer’s disease (Sperling et al 2009; Vlassenko et al. 2010) 
and glucose preference (Nugent et al. 2014a). Thus, regions of the brain that prefer glucose over 
ketones appear to be the same regions that remain functionally connected or synchronized when the 
brain is at rest, i.e. when a specific task is NOT being performed. Remarkably, these brain regions are 
the same ones that tend accumulate beta-amyloid later in life. This suggests that the vulnerability of 
certain brain regions to neuropathology later in life is linked in some way to metabolic fuel utilisation 
independently of age, even in young adults (Nugent et al. 2014a; Nugent et al. 2015).  
 


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Rationale 
If ketogenic supplements are to be exploited to prevent or delay brain fuel exhaustion, then 
establishing the long-term sustainability of ketogenesis becomes a critical therapeutic goal. Hence, a 
substance that is both ketogenic and anaplerotic and appropriate for human consumption is needed. 
Such a ketogenic-anaplerotic substance appears to exist in the form of triheptanoin which is a 
medium chain triglyceride composed of three seven carbon heptanoic acids on a glycerol backbone. 
Triheptanoin is more effective than its even-numbered homologue, trioctanoin, in animal models of 
both epilepsy (Borges and Sonnewald 2012; McDonald et al. 2014) and Alzheimer’s disease (Aso et al. 
2013).  
Oral daily triheptanoin has been shown to be safe and well-tolerated in children for months at a 
time (Pascual et al. 2014) as well as in adults (Roe et al. 2009). It is also more ketogenic than the more 
common 8 and 10 carbon even-chain medium chain triglycerides in children with pyruvate 
carboxylase deficiency (Mochel et al. 2005). Prior experience with classical even chain medium chain 
triglycerides and with triheptanoin shows that the dose should be up to 1 g/kg/day taken with meals. 
Medium chain triglycerides resolve some of the symptoms but are not a cure for diseases such as 
glucose transporter deficiency (Pascual et al. 2014), so the treatment regimen needs to be effective 
and well-tolerated over the long-term. As with the classical even-chain medium chain triglycerides, 
the adverse effects of triheptanoin are mostly gastrointestinal distress, and can usually be resolved by 
splitting up the daily dose, taking it with meals, gradual dose titration and efficient mixing with other 
foods.     
Hence, the principle that ketogenesis with anaplerosis would be more effective than ketogenesis 
alone is at least provisionally supported by a small but growing literature on the safety and efficacy of 
triheptanoin in clinical and pre-clinical research. To our knowledge, no one has yet reported using 
triheptanoin in humans with Alzheimer’s disease or mild cognitive impairment, so its application in 
these conditions is scientifically unproven but holds considerable potential. Hence, the BEAT7 Study 
will be a proof-of-principle for a new use of triheptanoin, i.e. a Phase 1b study aiming to delay the risk 
of cognitive decline in older people by bypassing or maybe correcting lower brain glucose uptake. In 
older people, brain glucose hypometabolism is particularly prevalent in the frontal cortex and is 
present before the onset of measurable cognitive decline (Nugent et al. 2015).  
 
3. PRELIMINARY DATA 
 
Ketogenic diet and dual tracer brain PET 
We now have a database with n>100 dual tracer (FDG and 11C-AcAc) PET scans in cognitively-
healthy younger and older people, some of which has been reported (Nugent et al. 2014a, 2014b; 
Castellano et al. 2015). Our CMR-G and CMR-A values for the brain as a whole, for grey and white 
matter and for specific brain regions in healthy controls are within expected limits so this is a robust, 
safe and well-validated protocol. The present study will be our first to use neuroimaging before and 
after triheptanoin. However, we have assessed brain fuel uptake in adults before and four days after a 
ketogenic diet and have shown that this treatment increases brain ketone uptake by ~8 fold 
(Courchesne-Loyer et al. 2015). These preliminary results clearly show that brain ketone uptake 
increases rapidly and markedly when ketone production is strongly but safely stimulated by a 
ketogenic diet. The advantage of our PET method is that we can quantify and compare ketone (CMR-
A) and glucose (CMR-G) uptake across multiple brain regions, which is essential to determining 
whether triheptanoin alters the regional glucose preference seen across the brain (Nugent et al. 


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2014a; Vlassenko et al. 2010). Our proposed dose of triheptanoin (1 g/kg body weight/day) is within 
the therapeutic target to bypass the 10% brain glucose uptake deficit seen in older people (Cunnane 
2011; Courchesne-Loyer et al 2013; Nugent et al. 2014a; 2014b; Nugent et al. 2015). Hence, we will be 
able to determine whether improved brain fuel uptake actually occurs in the regions experiencing 
glucose hypometabolism in older people. 
 
4. STUDY OBJECTIVE 
To use a multi-modal brain imaging portfolio to quantitatively assess whether brain energy 
metabolism (glucose and ketones), structure or functional connectivity change in older people with 
frontal glucose hypometabolism after 28 days on an oral dose of 1 g/kg/day of triheptanoin. 
 
5. STUDY HYPOTHESIS 
Our multi-modal brain imaging portfolio provides a unique opportunity to quantitatively assess 
whether brain energy metabolism (glucose and ketones), structure or functional connectivity change 
in older people with frontal glucose hypometabolism after 28 days on an oral dose of 1 g/kg/day of 
triheptanoin. 
  
6. STUDY DESIGN 
 
Overview 
It will be a Phase 1b study assessing 
a new purpose for triheptanoin in an 
older population. The intervention will 
last 28 days. The co-primary endpoints 
will be the quantitative change in brain 
ketone and glucose uptake measured 
using positron emission tomography. 
 
7. SELECTION AND WITHDRAWL OF 
PARTICIPANTS 
7a. Study population 
The target population will be people 
≥65 years old with frontal glucose 
hypometabolism as determined by 
FDG-PET. They will have no objective 
evidence of mild cognitive impairment 
or Alzheimer’s disease at screening.  
 
7b. Selection criteria 
Inclusion criteria:  
 Men and women ≥65 years old;  
 Score ≥26/30 on the Montreal Cognitive Assessment; 
 ≥10% lower brain glucose uptake in the frontal cortex as determined by PET imaging (Nugent et 
al. 2015). 


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Exclusion criteria:  
 Score <26/30 on the Montreal Cognitive Assessment; 
 Medications likely to affect the primary cognitive outcome; 
 Medical or psychiatric conditions that could interfere with study participation (Peterson et al. 
2005); 
 Fasting plasma glucose ≥7.0 mM (to avoid recruiting diabetics or pre-diabetics, both of which 
are risk factors for cognitive impairment in older persons (Mortimer et al. 2010) and also inhibit 
ketogenesis (Fukao et al. 2004); 
 Clinically-significant gastro-intestinal disease/conditions; 
 Clinically-significant liver disease/dysfunction : ALT ≥37 UI/L, AST ≥36 UI/L, Total bilirubin ≥26 
μmol/L; 
 Clinically-significant renal disease/dysfunction : creatinine ≥92 μmol/L, glomerular filtration 
rate <60 ml/min/1.73 m2 or >90 ml/min/1.73 m2; 
 Clinically-significant cardiac disease/conditions;   
 Clinically-significant abnormal coagulation laboratory results or coagulation disorders at 
screening; 
 Poorly controlled dyslipidemia (total cholesterol ≥6.2 mmol/L or triglycerides ≥2.20 mmol/L)  
 Hypertension: ≥140/90 mmHg; 
 Substance abuse; 
 Already on MCT supplementation; 
 Visual or hearing impairment impeding comprehension; 
 Non-French speaking; 
 Any condition with life expectancy less than 5 years; 
 Institutionalized or intending to move out of area within 1 year; 
 Participation in other intervention trials. 
 
7c. Participant recruitment and, screening 
Recruitment: Prospective participants will be recruited from our bank of over 50 older persons in 
whom FDG-PET has already been assessed. If necessary, participants will also be recruited using 
publicity in public spaces, radio, newspapers, bulletins and social media in the Sherbrooke area. Since 
prospective participants will lead essentially normal lives, memory clinics are not likely to be useful for 
recruitment. For individuals not wishing to participate in the study after screening, or who meet one 
or more of the exclusion criteria, the research nurse will only record age, gender, and reason for study 
exclusion.  
Screening: The screening will consist of a – (i) medical history, (ii) cognitive assessment to exclude 
those with prodromal or overt Alzheimer’s disease, and (iv) an FDG PET scan. Identification of 
individuals with mild cognitive impairment or Alzheimer’s disease will be based on the score on the 
Montreal Cognitive Assessment. Those scoring <26/30 on the Montreal Cognitive Assessment will be 
excluded.  
We have experience with routine cognitive testing to screen for declining memory or executive 
function associated with mild cognitive impairment in older people (Nugent et al, 2014a; Nugent et al, 
2014b, Castellano et al. 2015). The BEAT7 Study lead clinical investigator, Dr. Tamas Fulop, will 
confirm the appropriateness of each person invited to participate. We have planned for a 40% screen 
failure rate (Yurko-Mauro et al. 2010).  


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Control group: As a Phase 1b study in which the primary outcomes are based on imaging outcomes 
obtained pre- and post-intervention, no placebo or control group will be include in the project. 
Variation of the different outcome measures are unlikely to change significantly during one month 
without an intervention, as suggested by test-retest which show not significant difference after a 6 
month period. (Schaefer et al. 2000). 
   
7d. Intervention 
Triheptanoin group: The target daily dose of triheptanoin will be 1 g/kg/d, or approximately 70 g/d. 
It will be divided into four daily doses, one of which will be consumed at each meal and one with an 
evening snack. The triheptanoin is to be mixed with or blended into a variety of cold foods or drinks 
that have been shown to be effective for this purpose: plain or fat-free yogurt, whole grain hot cereal, 
fat-free cottage cheese, fat-free milk, fat-free low carb pudding, smoothie, applesauce or baby food.  
To improve tolerance and reduce the risk of side-effects, the dose of triheptanoin will be titrated 
upwards according to a previously tested schedule starting at 0.25 g/kg/day (about 4 g/meal) during 
days 1-7, increasing to 0.5 g/kg/day during days 8-14 (about 9 g/meal), increasing to 0.75 g/kg/day 
during days 15-21 (about 13 g/meal), and finally to 1.0 g/kg/day during days 22-28 (about 17 g/meal). 
Retention: Retention in the study will be encouraged by weekly meetings with the research nurse to 
collect the triheptanoin supplement and provide a blood sample for a measure of compliance.  
 
8. STUDY DURATION 
The triheptanoin will be given for 28±2 days. The two day leeway either way is to allow for last-
minute difficulties that can arise in scheduling the brain imaging. Brain ketone uptake increases within 
days of consuming a ketogenic diet (Courchesne-Loyer et al, 2015). However, the main effect of 
increased brain ketone uptake may be on a brain structural or functional parameter that takes longer 
to change than brain fuel uptake, so the study will last 28 days to try to capture effects on parameters 
measured using our neuroimaging portfolio.  
 
9. RESPONSE MEASURES 
 
9a. Co-primary outcome measures 
The co-primary outcomes will be change in global glucose uptake (CMR-G using FDG) and change in 
global ketone uptake (CMR-A using 11C-AcAc) uptake in grey matter after 28 days on the triheptanoin 
treatment compared to pre-treatment values.  
 
9b. Secondary outcome measures 
The secondary outcome measures will be change in post-treatment values versus pre-treatment 
values for: 
(i) CMR-A in the frontal cortex. 
(ii) CMR-G in the frontal cortex.  
(iii) MRI-based parameters: brain connectivity by rsfMRI, integrity of brain white matter tracts by 
dMRI, and regional brain volumes by vMRI. 
(iv) Cognitive score using the Montreal Cognitive Assessment.  
 
10. STUDY METHODS AND PROCEDURES 


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Events schedule 
 
Visit day 
 
0 
Day 7, 14, 21 
28 
Visit name 
Screening 
Baseline 
 
Completion 
    Written informed consent 
X 
 
 
 
    Demographics 
X 
 
 
 
    Medical history 
X 
 
 
 
    Montreal Cognitive Assessment 
X 
 
 
X 
    Blood sample for lab assessments1 
and vital signs (blood pressure, pulse) 
X 
X 
X 
X 
    FDG-PET2 
X 
 
 
 
    Neuroimaging3 
 
X 
 
X 
    Adverse events report4 
X 
X 
X 
X 
    Dispense supplement 
 
X 
X 
 
 
1 Plasma beta-hydroxybutyrate, acetoacetate, acylcarnitine profile, glucose, free fatty acids,  
   triglycerides, total cholesterol, lactate, complete blood count, electrolytes, pH, creatinine, and liver 
enzymes. 
2 Needed during screening unless participant already has an FDG-PET scan on file within the past 6 
   months. 
3 FDG and ketone PET; volumetric, functional and diffusion MRI 
4 All serious adverse events will be reported if and when they arise 
 
Written informed consent 
All prospective participants will provide written, informed consent prior to enrollment. 
 
Demographics, and medical history 
During screening a medical history including vital signs and anthropometry will be obtained by the 
research nurse associated with the BEAT7 Study. 
 
Neurological assessment 
Cognitive performance will be assessed at screening and at the end of the 28 day treatment period 
by the Montreal Cognitive Assessment. 
 
Laboratory assessments 
Blood samples will be collected for pre-screening and to measure compliance (See Events 
schedule). Cunnane’s lab does these analyses routinely (Nugent et al. 2014a; Castellano et al. 2015).  
 
Neuroimaging 
All prospective participants will undergo an FDG PET scan prior to enrollment; they will not be 
enrolled unless they have ≥10% lower brain glucose uptake in the frontal cortex.  
The PET component of our neuroimaging portfolio is essential for quantifying three aspects of 
brain fuel uptake in this study - (i) pre-intervention brain glucose uptake, (ii) whether brain glucose 
and/or ketone uptake increases post-triheptanoin, and (iii) whether the increase in brain fuel uptake 
post- triheptanoin occurs in brain regions that exhibited a glucose uptake deficit pre-triheptanoin. 
Brain fuel uptake will be quantified by dual tracer PET according to our routine protocol (Castellano et 


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al. 2015). Brain fuel uptake will be expressed as cerebral metabolic rate of glucose (CMR-G) or AcAc 
(CMR-A) in the units - μmol/100 g/min, as we have described recently (Castellano et al. 2015; Nugent 
et al. 2014a, 2014b). These are truly quantitative units to express brain fuel uptake. Although the 
calculation of CMR-G and CMR-A requires more blood samples and is more laborious that statistical 
methods used to measure brain fuel uptake, i.e. statistical parametric mapping, only the CMR-G and 
CMR-A values provide the actual magnitude of regional brain fuel uptake pre- and post-triheptanoin.  
The image acquisition protocol for the vMRI, rsfMRI and dMRI on our 3 Tesla MRI unit will follow 
our established protocols (Nugent et al. 2014; Castellano et al. 2015). vMRI-, rsfMRI- and dMRI-based 
markers will permit us to determine whether or not low brain glucose uptake pre-intervention or the 
possible change in brain glucose uptake post-intervention have related structural or functional 
components involving changes in white matter tracts or functional connectivity involving well-defined 
networks, i.e. the thalamo-cortical tract linking brain regions where brain glucose uptake is clearly 
deteriorating in Alzheimer’s disease (Castellano et al. 2015).  
 
11. SAMPLE SIZE  
As a Phase 1b study assessing a possible new use of triheptanoin, we do not have the necessary 
information to reliably calculate an effect size on the co-primary outcomes in this population. Hence, 
the sample size estimation is necessarily approximate; in our experience with analysing paired PET-
FDG and 11C-AcAc images in a pre- post-treatment study design, n=12 who complete the treatment 
should provide sufficient statistical power to observe significant differences between treatment in our 
co-primary outcomes (CMR-G and CMR-A) and in vMRI parameters such as regional brain volume and 
cortical thickness (Nugent et al. 2014a; Nugent et al. 2014b; Castellano et al. 2015). Other groups 
report similar effect sizes to ours for CMR-G with sample sizes of about 10 (Baker et al. 2011).  
 
12. CONCURRENT THERAPIES 
 
Permissible medication 
If a participant is taking prescribed medication permitted by this study design, they may continue 
to take it throughout the duration of the study. 
 
Rescue medication 
Prior studies have shown that high doses of triheptanoin can lead to gastrointestinal events (e.g., 
cramping, diarrhea, loose stools) or increased weight gain. No rescue medication will be given for side 
effects. In case of issues with tolerability or severe gastrointestinal distress, triheptanoin will be 
down-titrated by 25% for three days and then titration upwards will begin again if possible.  
 
13. COMPLIANCE WITH PROTOCOL 
At each weekly visit to monitor progress and receive the next weeks’ batch of triheptanoin, each 
participant will also provide a mid-morning blood sample 2-3 hours after having taken the first daily 
triheptanoin dose at breakfast. Along with other plasma metabolites, electrolytes and enzymes, 
plasma beta-hydroxybutyrate and medium chain acyl-carnitines will be measured as an objective 
indicator of compliance. Participants in whom plasma heptanoyl-carnitine is measurable on a weekly 
basis and who have achieved an average daily intake of ≥0.6 g/kg/d over ≥90% of the 28 day study 
period will be considered compliant and will be included in the data analysis.  


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14. STUDY WITHDRAWAL 
Participants may voluntarily withdraw from the study at any time. Participation will be 
discontinued if the study treatment is intolerable or unsafe, or if the participant develops any medical 
condition that in the opinion of the investigator would put a participant at an unacceptable medical 
risk or would compromise a participant’s ability to participate in the study. The reason for 
discontinuation will be documented. 
 
Study withdrawal criteria 
Participants will be discontinued from the study or receive no further study treatment if any one 
of the following criteria is met: 
 Participant unable or unwilling to continue to comply with study protocol. 
 Participant develops or has an exacerbation of any medical condition that in the opinion of the 
investigator would put the participant at an unacceptable medical risk or would compromise 
the participant’s ability to participate in the study. 
 Serum triglycerides higher than 2.20 mmol/L or serum total cholesterol higher than 
6.2 mmol/L . 
 A systolic pressure higher than 140 mmHg and a diastolic pressure higher than 90 mmHg. 
 Deteriorating liver function (ALT ≥ 37 UI/L, AST ≥ 36 UI/L, total bilirubin ≥ 26 μmol/L). 
 Deteriorating renal function (creatinine ≥ 92 μmol/L, glomerular filtration rate 
< 60 ml/min/1.73 m2 or > 90 ml/min/1.73 m2) 
 Clinically significant changes in other laboratory result  
 
15. STUDY MANAGEMENT 
The BEAT7 Study will be conducted at the Research Center on Aging, Université de Sherbrooke, 
Sherbrooke, Québec, Canada. It will be registered with Health Canada and with the Clinicaltrials.gov 
registry. The study will be conducted in accordance with applicable guidelines and regulations for 
Good Clinical Practice and will be approved by the Research Center on Aging’s Research Ethics 
Committee (REC) prior to initiation. The BEAT7 Study team will have regular weekly meetings to 
discuss all aspects of the study. The investigator will promptly report to the REC any new information 
that may adversely affect the safety of the participants or the conduct of the study. 
 
16. SAFETY 
Published clinical studies have shown that triheptanoin at 1 g/kg/d is safe for human use in both 
children and older adults (UX007 Investigators’ Brochure; Mochel et al. 2005; Roe et al. 2009; Pascual 
et al. 2014). The safety of the participants will be monitored at weekly laboratory assessments 
(complete blood count, liver function, blood lipid profile, renal function). Participants will be asked to 
report adverse events (AEs) during each weekly visit. All serious AEs (SAEs) will be reported to the REC 
and to Health Canada. In case of intolerance, the triheptanoin dose will be down-titrated to the 
previous dose for three days prior to titrating back to the higher dose. If the participant can maintain 
triheptanoin intake at ≥60% of the intended dose, they will be invited to continue in the study; if not 
they will be invited to discontinue.   
 


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Adverse events (AE) 
An AE is defined as any untoward medical occurrence in a study participant who is receiving an 
investigational product, and for which there may or may not be a causal link to the intervention. 
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE. An AE can therefore be any unfavourable and unintended sign (including 
laboratory result), symptom, or disease that is temporally associated with the investigational product, 
whether or not it is actually related to the investigational product. The presence of AEs will be 
assessed at each visit by direct questioning of the participant by a member of the BEAT7 Study team 
(usually the research nurse). The severity of any AE will be graded as mild, moderate or severe. The 
principal investigator will assess whether there is any relationship to the investigational product. All 
AEs will be followed up until resolved or until, in the opinion of the principal investigator, the AE is 
stabilized or has become chronic. The nature, severity, causality and course of the AE will be recorded 
in the study database using an Excel spreadsheet.  
 
Serious adverse events (SAE) 
A serious adverse event (SAE) is any untoward medical occurrence that, at any dose of the 
investigational product: results in death, is life-threatening, requires hospitalization or prolongation of 
existing hospitalisation, results in persistent or significant disability/incapacity, is a congenital 
abnormality or birth defect, or is an important medical event. Important medical events are those 
that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise 
the patient or may require intervention. SAEs will be reported to the study’s senior physician (Dr. 
Tamas Fulop) and to the REC as soon as possible.   
  
Clinical laboratory abnormalities and other abnormal assessments as AEs and SAEs 
Abnormal laboratory findings, i.e. clinical chemistry, haematology, and urinalysis, or other 
abnormal assessments, i.e. excessive weight gain or loss, or change in vital signs, that are judged by 
the investigator as clinically significant will be recorded as AEs or SAEs if they meet one of the 
definitions above. Clinically significant abnormal laboratory findings or other abnormal assessments 
that are detected during the study or are present at baseline and significantly worsen following start 
of the study will be reported as AEs or SAEs. However, clinically significant abnormal laboratory 
findings or other abnormal assessments that are associated with a disease reported in the medical 
history (unless judged by the investigator as more severe than expected for the participant’s 
condition) or that are present or detected at the start of the study and do not worsen following start 
of the study, will not be reported as AEs or SAEs. The investigator will exercise medical judgement in 
deciding whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. 
 
Time period, frequency, and method of detecting AEs 
All AEs and SAEs will be recorded from the time of consent. Each participant will be monitored 
regularly by the investigator and study personnel for AEs and SAEs occurring throughout the BEAT7 
study. 
 


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Recording of AEs and SAEs 
When an AE/SAE occurs, the principal investigator will review all documentation (hospital, 
laboratory, diagnostic reports) relative to the event. The investigator will then record all relevant 
information regarding an AE or SAE in the appropriate form. For each SAE, start and stop dates, action 
taken, outcome and relationship to study product (causality) must be documented. The investigator 
will attempt to establish a diagnosis of the event based on signs/symptoms and/or other clinical 
information. In the absence of a diagnosis, the individual signs/symptoms should be documented. All 
details of any treatments initiated due to the SAE will be recorded in the participant’s notes and 
entered in the study database using an Excel spreadsheet as required by our REC. 
 
Prompt reporting of SAEs 
SAEs require prompt action. Once a member of the team becomes aware that an SAE has occurred, 
the study coordinator and investigator will be notified within one working day. The study SAE form 
will be completed as thoroughly as possible with all available details of the SAE, signed by the 
investigator or appropriately qualified designee, and transmitted to the study database and to the 
REC within one working day of first becoming aware of the SAE. Even if all information concerning the 
SAE is not yet available, notifying the investigator and the REC will not be delayed before completing 
the information form to the extent possible; the form will be updated as soon as possible.  
The investigator will always provide an assessment of causality at the time of the initial report (see 
Assessment of Causality below). If data obtained after reporting the AE indicate that the assessment 
of causality was incorrect, then the SAE form will amended, signed, dated and resubmitted.  The 
investigator will also notify the REC in accordance with requirements. The investigator and others 
responsible for participant care should institute any supplementary investigations of SAEs based on 
their clinical judgement of the likely causative factors. This may include seeking further opinion from a 
specialist in the field of the AE or requesting extra tests. If a study participant dies, date of death and 
any post-mortem findings, including histopathology will be provided if available. 
The investigator will submit a report on the SAE to the REC, Health Canada and Ultragenyx as per 
the regulations within the stipulated timelines. 
 
Evaluating AEs and SAEs 
Assessment of Intensity: The investigator will make an assessment of intensity for each AE and SAE 
reported during the study. The assessment will be based on the investigator’s clinical judgement. The 
intensity of AEs and SAEs will be assigned to one of the following categories: mild (an event that is 
easily tolerated by the participant, causing minimal discomfort and not interfering with everyday 
activities); moderate (an event that is sufficiently discomforting to interfere with normal daily 
activities); severe (an event that is incapacitating and prevents normal daily activities). 
Assessment of Causality: The investigator will assess the relationship between the investigational 
product and the occurrence of each AE or SAE. The investigator will use clinical judgement to 
determine this relationship. Alternative causes such as natural history of underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to consuming the 
investigational product will be considered and investigated. The investigator will also consult the 
Investigator Brochure for UX007 in making this assessment. 
The causal relationship to the investigational product will be assessed using the following 
classifications: Not related (in the investigator’s opinion, there was not causal relationship between 


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the investigational product and the AE); Unlikely (the temporal relationship between the AE and the 
investigational product is such that the latter is not likely to have had any reasonable association with 
the AE); Possible (the AE could have been caused by the participant’s clinical state or the 
investigational product); Probable (the AE follows an reasonable temporal sequence rom the time of 
investigational product administration, abates upon discontinuation of the investigational product, 
and cannot reasonably be explained by the known characteristics of the participant’s clinical state); or 
Definitely (the  AE follows a reasonable temporal sequence from the time of investigational product 
administration or reappears when the investigational product is reintroduced). 
There may be situation in which an SAE has occurred and the investigator has minimal information 
to include in the initial report. However, the investigator will always make an initial assessment of 
causality for every AE prior to transmission of the SAE form. The opinion of the investigator may 
change in light of follow-up information and the SAE form will be amended accordingly. The causality 
assessment is one of the criteria when determining regulatory reporting requirements. 
Assessment of Expectedness: Expected (An AE the nature or severity of which is consistent with the 
applicable information on the investigational product for an unapproved medicinal product (i.e. 
Investigators’ Brochure for UX007); Unexpected (An AE the nature of which is not consistent with 
information on the investigational product in the Investigators’ Brochure for UX007). 
 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator will actively follow each participant and provide 
further information on the participant’s condition. All AEs and SAEs documented at a previous 
visit/contact and that are designated as ongoing, will be reviewed at subsequent visits/contacts. All 
AEs and SAEs will be followed up until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up. The investigator will ensure that 
follow-up includes any supplemental investigations as may be indicated to elucidate the nature 
and/or causality of the AE or SAE. This may include additional laboratory tests or investigations or 
consultation with other healthcare professionals. 
 
17. DATA ANALYSIS 
We routinely analyze dual tracer PET scans with Freesurfer and PMOD software (Castellano et al. 
2015; Nugent et al. 2014a; Nugent et al. 2014b; Nugent et al. 2015). Image acquisition protocols and 
analysis pipelines to quantify brain fuel uptake and MRI-based measures (regional vMRI, rsfMRI, 
dMRI) will be supervised by the study co-investigators, Drs. Whittingstall and Descoteaux. All region-
based brain PET and MRI analyses will undergo a p≤0.05 false discovery rate correction for multiple 
comparisons (Nugent et al. 2014a, 2014b). Water diffusion (diffusivity), fractional anisotropy (broadly 
inversely correlated to diffusivity) and apparent fiber density will be mapped along major white 
matter bundles, thalamo-cortical connections, as well as in regions initialized from PET-detected 
regions of interest. Global and regional grey matter differences for CMR-A and CMR-G pre- to post-
intervention will be assessed using the general linear model framework implemented in the 
commercially-available SPM8 (Matlab, MathWorks, Natick, MA, USA). 
 
Expected outcomes 
For the co-primary outcomes, we can expect increased CMR-A at the end of the triheptanoin 
supplementation period. We have not seen increased CMR-G after four days on a high fat ketogenic 


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diet (Courchesne-Loyer et al. 2015), but this may still occur after 28 days on triheptanoin. We do not 
expect to see any cognitive changes both because of the short duration of the intervention and 
because of the normal cognitive status of the participants.  
 
Interpretation of results 
These results will contribute to knowing the safety of triheptanoin in older people and its effect on 
brain uptake of glucose and acetoacetate. We may also learn whether resting state functional 
connectivity or white matter integrity changes after triheptanoin. These results may provide a 
rationale for a future triheptanoin intervention in older people with mild cognitive impairment or 
Alzheimer’s disease in with cognitive performance as the primary outcome.  
 
18. DATA COLLECTION AND STORAGE 
The master list with participant names and numbers and all study documents will be securely 
stored by the principal investigator. Data specific to the BEAT7 Study participants will be 
denominalized and stored electronically. Direct access to the individual denominalized data will be 
strictly limited to the researchers who are directly involved in the study (authorized investigators, 
collaborators, study coordinator, research assistant, statistician, students) and only for the purposes 
of the study. The BEAT7 Study will be conducted in accordance with all applicable electronic record 
and data capture regulations. All study records will be retained for 25 years in accordance with Health 
Canada regulations (C.05.012 [3]). 
 
 


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19. REFERENCES 
 
Aso E, Semakova J. et al. (2013) Triheptanoin supplementation to a ketogenic diet curbs cognitive 
impairment in APP/PS1 mice used as a model of familial Alzheimer’ disease. Current Alzheimer Res 10, 
290-297. 
Baker, L. D., Cross, D. J., et al. (2011) Insulin resistance and Alzheimer-like reductions in regional 
cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. 
Archives of Neurology 68(1) 51-57.  
Borges K, Sonnewald U (2012) Triheptanoin - a medium chain triglyceride with odd chain fatty acids: a 
new anaplerotic anticonvulsant treatment? Epilepsy Res. 2012 Jul;100(3):239-44 
Brunengraber H, Roe CR. (2006) Anaplerotic molecules: current and future. J Inherit Metab Dis. 2006 
Apr-Jun;29(2-3):327-31. 
Castellano CA, Nugent S, Paquet N, Tremblay S, Bocti C, Lacombe G, et al. (2015) Lower Brain 18F-
Fluorodeoxyglucose Uptake But Normal 11C-Acetoacetate Metabolism in Mild Alzheimer's Disease 
Dementia. J Alzheimer Dis. 2014 Aug 21. [Epub ahead of print] PMID: 25147107.  
Couch, S. C., Schwarzman, F., et al. (1999) Growth and nutritional outcomes of children treated with 
the ketogenic diet. J Am Diet Assoc 99(12) 1573-1575.  
Courchesne-Loyer A, Fortier M, Castellano CA, Nugent S, Cunnane SC (2015). Brain ketone uptake 
during acute moderate ketosis. Poster at BRAIN 2015 Conference, Vancouver, June 27-30, 2015.  
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