Clinical trial NCT02036853
Conditions: Glucose Transporter Type-1 Deficiency Syndrome (Glut1 DS)
Keywords: Triheptanoin Glut1 DS Epilepsy Seizures
Sponsor: Adrian Lacy
Start date: 2014-02-20; Completion date: 2019-06-30
Enrollment: 20 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is being done to assess the safety and long-term efficacy of triheptanoin in pediatric patients with Glut1 DS over a 5-year treatment period. Glut 1 is a protein that helps transport glucose to the brain. Glucose is the brain's primary source of energy. Glut 1 DS prevents this protein from being effectively produced, causing deprivation of energy to the neurons of the of the brain.

Glut1 DS is a severely debilitating disease characterized by seizures, developmental delay and movement disorder. There are currently no approved treatments specific to Glut1 DS. Treatment generally includes medications for control of seizures. The use of a ketogenic diet can be effective in controlling seizures when medications are ineffective or provide insufficient control. However, the ketogenic diet may be very difficult for patients to maintain for long periods of time, and there may be negative secondary long-term effects of ketogenic diet.. Triheptanoin is metabolized to molecules that can provide an alternative energy source to the brain, and appears to help in controlling seizures without many of the difficulties of the ketogenic diet.

Eligible patients may be those who have been diagnosed with GLUT1 DS, and have discontinued or are not currently on ketogenic diet, or are able to tolerate triheptanoin if they have been treated or are currently being treated with triheptanoin and do not qualify for any other clinical trial.

Detailed description:
Triheptanoin is proposed for the treatment of seizures in glucose transporter type-1 deficiency syndrome (Glut1 DS). Glut1 DS is a rare disease with an estimated US prevalence of \~3,300.

The proposed study is an open-label study to assess the safety and long-term efficacy of triheptanoin in patients with Glut1 DS over a 5-year treatment period. Eligible patients may be those who are able to tolerate triheptanoin if they have been treated or are currently being treated with triheptanoin and do not qualify for any other clinical trial. Subjects previously treated with triheptanoin will continue to dose at approximately 35% of total daily calories (\~1-4g/kg/day, depending on age). Subjects who are naïve to triheptanoin will begin a 2-week fixed titration schedule up until they have reached 35% of total daily calories.

The primary objective of the study is to evaluate the safety of triheptanoin via adverse event rates and laboratory values. The secondary objective is to evaluate the long-term efficacy of triheptanoin as measured by the change in seizure frequency from historical baseline.

Arms: arm 1: Subjects previously treated with triheptanoin arm 2: Naïve to triheptanoin
Interventions: intervention 1: Triheptanoin
Intervention descriptions: intervention 1: Schedule A: Subjects previously treated with triheptanoin will continue to dose at approximately 35% of total daily calories (\~1-4g/kg/day, depending on age).

Schedule B: Subjects who are naïve to triheptanoin will begin a 2-week fixed titration schedule up until they have reached 35% of total daily calories (\~1-4 g/kg/day depending on age). If a subject has not reached the target of 35% of total daily calories, by the end of the 2-week fixed titration period, dose titration should continue until achieved or until the maximally tolerated dose has been established.

Protocol documents:
Prot_SAP_000.pdf: 
Study Title: 
Investigational Product: 
Indication: 
IND Number:
NCT Number: 
Sponsor: 
Primary Investigator: 
An Open-Label Trial of Triheptanoin in Patients with 
Glucose Transporter Type-1 Deficiency 
Syndrome(GLUT1 DS) 
Triheptanoin 
Glucose Transporter Type-1 Deficiency Syndrome 
(GLUT1DS) 
120505 
02036853
Cook Children’s Medical Center 
Adrian Lacy, MD 
Cook Children’s Study Number: 2013-NEUR-001 
Protocol Version Date: 
Company: 
Study Site: 
Phase of Development: 
Version 4.1, 23-Mar-2018 
Ultragenyx Pharmaceutical, Inc.  
Cook Children’s Medical Center, 801 7th Ave, Fort 
Worth, TX 76104 
Phase 2 
IRB NUMBER: 2013-034
IRB APPROVAL DATE: 04/04/2019
IRB EXPIRATION DATE: 04/03/2020


Protocol Number:  2013-NEUR-001 
Version: 4.1 
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TABLE OF CONTENTS 
 
SECTION  
PAGE 
 
1.0 STUDY OBJECTIVES 
4 
 
1.1 Primary Objectives 
4 
 
1.2 Secondary Objectives 
4 
 
 
 
2.0 BACKGROUND AND SIGNIFICANCE 
4-7 
 
2.1 Disease Background 
4 
 
2.2 Supporting Previous Studies 
4 
 
2.3 Protocol Rationale 
7 
 
 
 
3.0 STUDY DESIGN 
7-8 
 
3.1 Study Population 
7 
 
3.2 Number of Subjects Planned 
7 
 
3.3 Study Timeline 
8 
  
 
4.0 SELECTION AND ENROLLMENT OF SUBJECTS 
9-10 
 
4.1 Inclusion Criteria 
9 
 
4.2 Exclusion Criteria 
9 
 
4.3 Consent Procedures 
10 
 
  
 
5.0 METHODS 
10-13 
 
5.1 Recruitment of Subjects 
10 
 
5.2 Sources of Research Material 
10 
 
5.3 Duration of Treatment 
11 
 
5.4 Study Procedures 
11 
  
 
6.0 OBSERVATIONS AND MEASUREMENTS 
14-16 
 
6.1 Vineland Adaptive Behavior Scales, Second Edition 
14 
 
6.2 Barry-Albright Dystonia Scale 
14 
 
6.3 The Pediatric Quality of Life Inventory Scale 
15 
 
6.4 Columbia Suicide Severity Rating Scale 
15 
 
6.5 Tracking Diary 
16 
 
 
 
 
 
 
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PAGE 
7.0 CRITERIA FOR EVALUATION 
17 
 
7.1 
Safety 
17 
 
7.2 
Safety Monitoring 
17 
 
7.3 
Efficacy 
17 
 
 
 
8.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND 
OFF STUDY CRITERIA 
17 
  
 
9.0 POTENTIAL RISKS & BENEFITS 
17-18 
  
 
10.0 DATA COLLECTION AND ADVERSE EXPERIENCE REPORTING 
18-20 
 
10.1 Clinical Data Collection 
18 
 
10.2 Data Management 
18 
 
10.3 Data Storage 
19 
 
10.4 Procedures to Maintain Confidentiality 
19 
 
10.5 Quality Assurance 
19 
 
10.6 Adverse Event Reporting 
20 
 
  
 
11.0 STATISTICAL CONSIDERATIONS 
21-22 
 
11.1 Safety Analysis 
21 
 
11.2 Efficacy Analysis 
21 
 
 
 
 
12.0 HUMAN SUBJECTIONS 
22 
 
12.1 Institutional Review Board (IRB) Review and Informed Consent 
22 
 
12.2 Study Modifications/Discontinuation 
22 
 
  
 
 
  
 
 
 
IRB NUMBER: 2013-034
IRB APPROVAL DATE: 04/04/2019
IRB EXPIRATION DATE: 04/03/2020


Protocol Number:  2013-NEUR-001 
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An Open-Label Trial of Triheptanoin in Patients with Glucose Transporter Type-1 
Deficiency Syndrome (GLUT1 DS) 
 
1.0  
GOALS AND OBJECTIVES 
 
1.1  
The primary objective of the study is: 
 To evaluate the safety of triheptanoin via adverse event rates and laboratory 
values. 
1.2  
The secondary objective of the study is: 
 To evaluate the long-term efficacy of triheptanoin as measured by the change in 
seizure frequency from historical baseline. 
 
2.0  
BACKGROUND AND SIGNIFICANCE 
 
2.1  
Disease Background 
 
Glucose Transporter Type-1 Deficiency Syndrome (GLUT1 DS) is a devastating disease 
characterized by seizures, developmental delay and movement disorder.1 It is caused by a 
mutation in solute carrier family 2, member 1 gene (SLC2A1), which encodes for glucose 
transporter type-1.  This protein transports glucose from blood into the brain.  Because 
glucose is the primary source of energy for the brain, this disorder results in a chronic state of 
energy deficiency in the brain.  Current treatment consists of ketogenic diet, which generates 
ketone bodies that provide an alternative energy source to glucose.1,2 However, ketogenic 
diet is difficult to tolerate and some patients are not compliant with or are otherwise not on 
the diet.  As such, in order to improve control of break-through seizures, patients may require 
one to two antiepileptic drugs (AEDs).  
 
2.2  
Supporting Previous Studies 
 
2.2.1  Nonclinical Studies 
 
Triheptanoin, which is the name of the substance to be provided by the Company and is 
under investigation in this trial, is synonymous with other names for the same 
substancewhich have been the subject of investigations published in the scientific and 
medical literature.  A number of in vitro and rat studies have been conducted with 
triheptanoin by research investigators.4-8 Triheptanoin is likely hydrolyzed in the intestine 
and the heptanoate and glycerol absorbed efficiently in the rat liver. The 7 carbon heptanoate 
is cleaved to two acetyl-CoA and one propionyl-CoA. These are metabolized to several 
possible compounds including C4 and C5 ketone bodies, which can distribute via the 
circulation and can be taken up by the brain and muscle. Some propionyl-CoA will be 
converted to succinyl-CoA to refill the TCA cycle, and some will be converted, via the TCA 
cycle, to oxaloacetate to generate glucose via gluconeogenesis.  
IRB NUMBER: 2013-034
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In a study of the biochemical effects of triheptanoin in the brains of a mouse model of 
GLUT1 DS, gluconeogenesis in the brain was established based on the presence of 
radiolabeled glucose after intravenous infusion of radiolabeled heptanoate.8 In addition, 
intravenous infusion of radiolabeled heptanoate led to higher levels of acetyl-CoA and 
glutamine in the brain of G1D mice relative to normal mice. Brain glutamine concentration 
and 13C enrichment were also greater when compared with glutamate in both animal groups, 
suggesting that heptanoate and/or C5 ketones were primarily metabolized by glia.  The 
effects of triheptanoin on the seizure activity in this mouse model have not yet been reported. 
 
Triheptanoin has been found to be effective in 4 of 7 animal models of epilepsy.  In the 
corneal kindling chronic model, triheptanoin delayed development of kindled seizures in a 
dose-dependent manner, but did not protect against fully kindled seizures.9  In the chronic 
model of PTZ (pentylenetetrazole) in pilocarpine-status epilepticus, triheptanoin partially 
reversed the lowered PTZ threshold for tonic seizures but not clonic seizures in the chronic 
stage.9  In the maximal electroshock threshold model, triheptanoin increased the seizure 
threshold.10 In the genetic mouse model of generalized epilepsy due to the GABA-A-
gamma2(R43Q) mutation, triheptanoin halved the time spent in seizures and reduced the 
frequency of seizures caused by insulin-induced hypoglycemia.11  However, triheptanoin was 
not effective in the fluorothyl, pentylenetetrazole nor 6Hz  models.10  The efficacy of 
triheptanoin in some but not all animal models of epilepsy is similar to that found with other 
AEDs.8 
 
In toxicology studies, there were no toxic effects on animal growth, lipid digestibility, 
clinical chemistry parameters, or the histopathology of liver, kidney and small intestine in 
rats fed for 9 months with triheptanoin at levels that replaced up to 50% of the standard 
soybean oil in rodent chow.  Hepatic steatosis and alterations in intestinal villi were the only 
findings observed in a single 9 month repeat dose oral rat toxicology study.12 The findings 
may be due to the effect of extreme fat overload compared with the normally low fat intake 
in rats (~10-fold normal fat intake) and the efficient direct absorption, non-bile-dependent of 
triheptanoin and metabolites. This adverse effect has not been observed in previous human 
clinical trials in which FAOD patients have shown the opposite finding, a reduction in 
hepatomegaly/steatosis, with triheptanoin treatment.   
 
2.2.2 Clinical Studies 
 
Approximately 130 subjects with various disorders, including fatty acid oxidation disorders 
(FAOD), Adult Polyglucosan Body Disease, pyruvate carboxylase deficiency, Pompe 
disease, Congestive Heart Failure, Huntington Disease, and GLUT1 DS, have been treated 
with triheptanoin for periods of up to 13 years.13-15Triheptanoin treatment has been well 
tolerated by subjects with these disorders. 
 
IRB NUMBER: 2013-034
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Triheptanoin has been most extensively studied in long-chain FAOD (LC-FAOD) and has 
improved a wide range of LC-FAOD symptoms in the subjects studied.  For example, three 
subjects with very long-chain acyl-CoA dehydrogenase (VLCAD) had numerous clinical 
problems, including cardiomyopathy, hepatomegaly with associated hypoglycemia, and 
muscle pain with Gowers’ sign, despite receiving standard of care treatment.13  These 
problems improved within hours to weeks of initiating triheptanoin  treatment.   
 
Similarly, 48 subjects with FAOD, including 43 with LC-FAOD, experienced a large number 
of important beneficial effects of triheptanoin treatment in different body systems, including 
improvement of problems in the heart (arrhythmia or cardiomyopathy), muscle 
(rhabdomyolysis and weakness), and liver (hypoglycemia and hepatomegaly).14 During the 
study, 6 of the 59 FAOD subjects (10%) died (including 1 subject who had not been 
compliant with any therapy).  The mortality rate of 6 deaths in 59 triheptanoin -treated LC-
FAOD subjects is approximately 10% and is much less than the 50% mortality rate in 
patients treated with standard of care,16 although cross-study comparisons need to be 
interpreted with caution.   
 
None of the 21 subjects from this group who continued on long-term triheptanoin treatment 
for total periods of up to 13 years has died.  Improvements have continued in these subjects. 
For example, cardiomyopathy fully resolved in six of nine subjects with cardiomyopathy; 
two others improved and one subject with advanced cardiomyopathy requiring heart 
transplant worsened.17 Follow-up discussion with Dr. Gerard Vockley revealed that the heart 
transplant subject has continued on triheptanoin and is stable.  
 
Triheptanoin has been generally well tolerated when administered to subjects with all 
subtypes of FAOD.  Some subjects have had difficulties with gastrointestinal upset or have 
diarrhea when taking the oil.  Small doses and mixing with foods or drinks is important in 
tolerability.  Many of the serious adverse events (SAEs) reported for these subjects involved 
events consistent with FAOD (e.g., muscle weakness or pain, myoglobinuria, 
rhabdomyolysis, metabolic crisis or decompensation, cardiomyopathy, hypoglycemia, 
elevated CK), often in association with events known to precipitate metabolic crises in these 
patients, such as infections (e.g., upper respiratory infection, flu, cold, urinary tract infection, 
gastrointestinal illness) or exercise, or during periods of limited triheptanoin  treatment.  
Other SAEs involved events such as infections without reported FAOD exacerbation, fever 
and/or vomiting from unspecified cause, respiratory distress/breathing problems, falling 
oxygen saturation rate, seizure, or medical procedures apparently unrelated to FAOD.  
Almost all of the reported SAEs were considered unrelated to triheptanoin treatment. 
Triheptanoin has been administered in 44 pediatric subjects with LC-FAOD. Of these, three 
subjects had treatment initiated between the ages of 0-1 month, eight between ages 1 month-
2 years, 29 between ages 2-12 years, and four between ages 12-16 years. Twenty of these 
subjects had triheptanoin treatment for over five years.  The safety profile in pediatric 
subjects is similar to that found in adults, with ADR consisting of GI disturbance and excess 
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weight gain (Section 5.4 of Investigator Brochure). 
 
Triheptanoin is being studied in approximately 30 GLUT1 DS subjects in a clinical trial 
sponsored by Dr. Juan Pascual at the University of Texas, Southwestern.  The study is 
ongoing and no results have been published, although public reports from patient families 
have suggested significant benefit in seizure reduction and development improvement.  
 
2.3 
Protocol Rationale 
 
GLUT1 DS results in insufficient transport of glucose into the brain.  The rationale for 
triheptanoin treatment in GLUT1 DS is that:   
 
1) Triheptanoin is metabolized to heptanoate and C4 and C5 ketone bodies.  These 
metabolites provide an alternative energy source to the brain  
 
2) Triheptanoin has the ability to provide succinyl-CoA via propionyl-CoA in order 
to resupply intermediates of the citric acid cycle (i.e., anaplerosis).  In contrast, 
ketogenic diet and medium chain triglyceride (MCT) oil provide only even-
carbon chain ketone bodies and fatty acids, neither of which can be anaplerotic   
 
3) Triheptanoin treatment has the additional potential advantage over ketogenic diet 
in that ketogenic diet requires severe restriction of carbohydrate intake, which 
leads to reduced serum glucose; this state of low normal serum glucose further 
exacerbates the glucose deficiency in the brain and partially offsets the benefits of 
ketone body generation.  In contrast, triheptanoin treatment allows for greater 
carbohydrate intake and higher serum glucose levels relative to ketogenic diet and 
thus does not exacerbate the deficiency of glucose transport into the brain. 
 
Because of the difficulties in maintaining a ketogenic diet, some patients are not able to 
comply with or tolerate the diet.  These patients represent the subgroup of GLUT1 DS 
patients who are most in need of an alternative therapy to ketogenic diet.   
 
3.0  
STUDY DESIGN 
 
This is an open-label study to assess the safety and efficacy of triheptanoin in patients with 
GLUT1 DS over a four (4)-year initial treatment period with a one (1)-year extension period.  
 
3.1 
Study Population 
 
The study will enroll GLUT1 DS patients (between 1 and 50 years of age) who are currently 
not on ketogenic diet or medium chain triglycerides (MCT).  Eligible patients may be those 
who (1) have participated in a prior clinical trial of triheptanoin, or (2) are naïve to 
IRB NUMBER: 2013-034
IRB APPROVAL DATE: 04/04/2019
IRB EXPIRATION DATE: 04/03/2020


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Version: 4.1 
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Screening 
Period
• 2 weeks
Initial 
Treatment 
Period
• Visit 1
• Day 1
Initial 
Treatment 
Period
• Visit 2
• 13 weeks
Initial 
Treatment 
Period
• Visit 3
• 26 weeks
Initial 
Treatment 
Period
• Visit 4
• 52 weeks
Initial 
Treatment 
Period
• Visit 5
• Year 2, 26 
weeks
Initial 
Treatment 
Period
• Visit 6 
• Year 2, 52 
weeks
Initial 
Treatment 
Period
• Visits 7-8
• Years 3&4
End of 
Study
• Visit 9
• Year 5
Screening 
Period
• 2 weeks
Initial 
Treatment 
Period
• Visit 1
• Day 1
Initial 
Treatment 
Period
• Phone  Visit
• 2 weeks
Initial 
Treatment 
Period
• Visit 2
• 13 weeks
Initial 
Treatment 
Period
• Visit 3
• 26 weeks
Initial 
Treatment 
Period
• Visit 4
• 52 weeks
Initial 
Treatment 
Period
• Visit 5-6
• Year 2, 26 
&52 weeks
Initial 
Treatment 
Period
• Visits 7-8
• Years 3-4
End of 
Study
• Visits 9
• Years 5
triheptanoin and not eligible for another trial.  
 
3.2 
Number of Subjects Planned 
 
The study will enroll up to 50 subjects in total.  
 
3.3 
Study Timeline 
 
The total duration for individual subjects is five (5) years, including four(4) years with eight 
(8) visits to the clinical site during the initial treatment period and one (1) additional year in 
the extension period.  After a two-week Screening period, subjects will enter the initial 
treatment period on one of two schedules. Study Visit window will be +/- 2 weeks from the 
scheduled date. 
 
3.3.1 Schedule A:  
 
For subjects previously treated with triheptanoin the visit schedule will be as follows, 
with telephone follow-up between visits as needed: (Table 1) 
 
 
 
 
 
 
 
3.3.2 Schedule B: 
 
For subjects who are naïve to triheptanoin, the visit schedule will be as follows with 
telephone follow-up between visits as needed:(Table 2) 
 
 
 
 
 
 
 
 
IRB NUMBER: 2013-034
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4.0  
SELECTION AND ENROLLMENT OF SUBJECTS 
 
4.1  
Inclusion Criteria 
 
Individuals eligible to participate in this study must meet all of the following criteria: 
 
1) Patients with GLUT1 DS by physician diagnosis 
2) Males and females, aged 1 to 50 years 
3) Allowed to be on concomitant AEDs 
4) Patients are able to tolerate triheptanoin if they have been (or are currently being) 
treated with this medication 
5) Must, in the opinion of the investigator, be willing and able to comply with study 
procedures and schedule 
6) Provide written assent (if appropriate) and written informed consent by a Legally 
Authorized Representative (LAR) after the nature of the study has been explained, 
and prior to any research-related procedures 
7) Sexually active subjects must be willing to use an acceptable method of contraception 
while participating in the study 
8) Females of childbearing potential must have a negative pregnancy test at Screening 
and be willing to have additional pregnancy tests during the study 
 
4.2  
Exclusion Criteria 
 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
 
1) Patients and their Legally Authorized Representatives (as appropriate) not willing or 
able to give writtenor verbal assent or written informed consent. 
2) Concomitant administration of a ketogenic diet for the treatment of GLUT1 
deficiency at time of study drug initiation 
3) Concomitant administration of valproic acid 
4) In the Investigator’s opinion, the patient may not be compliant 
5) Pregnant or breastfeeding an infant at screening 
6) Has a concurrent disease or condition, or laboratory abnormality that, in the view of 
the Investigator, places the subject at high risk for adverse events, or introduces 
additional safety concerns  
7) History of or current suicidal ideation, behavior and attempts 
8) Patient qualifies for any other clinical trial designed to progressively evaluate the 
safety and efficacy of triheptanoin as approved by the FDA under a separate IND  
which is open at Cook Children’s 
 
 
 
IRB NUMBER: 2013-034
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4.3  
Consent Procedures 
 
Informed consent and assent will be obtained following an informed consent conference 
wherein the principal investigator or their IRB-approved designee will discuss with the LAR 
the purpose of the study, procedures to be followed, the duration of participation, alternate 
modes of treatment, and the risks and benefits of participation, as described in the consent 
form.  
 
A signed consent form will be obtained from the LAR for each enrolled subject. As per the 
Cook Children’s IRB guidelines, written assent from a minor aged 13-18 and verbal assent 
from a minor aged 8-12 will be obtained. The patient and LAR will be provided written 
copies of both the informed consent and assent documents. The signed original consent and 
assent documents will become a part of the permanent medical record and copies will be 
provided to the patient and LAR. A consent note will be completed and placed in the 
subject’s research chart to document properly-obtained consent.  
 
This study will be conducted in compliance with all United States Federal and local laws, 
regulations, and guidelines for the conduct of research in a vulnerable population. 
 
5.0  
METHODS 
 
5.1 
Recruitment of Subjects 
 
Eligible patients will be identified either from the outpatient neurology clinic or inpatient 
neurology population at Cook Children’s Medical Center; or patients who are referred for 
treatment for their GLUT 1 DS. Recruitment of subjects will be performed by the principal 
investigator or their IRB-approved designee.  
 
5.2 
Sources of Research Material 
 
5.2.1 Investigational Product  
 
An investigational form of triheptanoin will be utilized as study drug. This form of 
triheptanoin is a highly purified form intended for oral administration. It is a medium chain 
triglyceride of three seven-carbon fatty acids whose formula is:3 
 
IRB NUMBER: 2013-034
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This investigational form of triheptanoin is being developed by Ultragenyx 
PharmaceuticalInc. as a substrate replacement therapy for the treatment of long-chain fatty 
acid oxidation disorders (LC-FAOD) and GLUT1 DS. 
 
5.2.2 Mechanism of Action 
 
Triheptanoin is metabolized to heptanoate and C4 and C5 ketone bodies.  These metabolites 
bypass the GLUT1 transporter to cross the blood-brain-barrier and provide an alternative 
energy source to the brain. These metabolites also have the ability to provide succinyl-CoA 
via propionyl-CoA in order to resupply intermediates of the citric acid cycle (i.e., 
anaplerosis) within the brain. 
 
5.2.3 Dose and Mode of Administration 
 
Triheptanoin is colorless to light yellow oil. Triheptanoin will be administered orally (PO) 
with food or by gastrostomy tube at least four times per day (breakfast, lunch, dinner, and 
before bed), comprising 35-40% of total calories titrated to a maximum tolerated dose level. 
The dose may be divided into smaller more frequent doses with food as needed. The dose 
may be mixed with small amounts of food or drink as indicated in the administration 
guideline provided by Ultragenyx. 
 
The rationale for the chosen dose (1-4 g/kg of body weight per day divided into 4 doses) is 
based on the demonstrated safe and effective use of triheptanoin at the suggested dose in 
patients with Fatty Acid Oxidation Disorders.14 
 
 
5.3 
Duration of Treatment 
 
Duration of the initial treatment is 4 years with an additional one-year extension period. 
 
Triheptanoin will be provided to the patient by the CCMC Investigational Drug Service 
pharmacy (IDS pharmacy) during visit 1 and at all scheduled clinic visits. In lieu of 
dispensation at time of study visit, the IDS pharmacy may choose to ship either a 3-month or 
6-month supply to patients, as prescribed by the PI. 
 
5.4 
Study Procedures  
 
The dose will be ~35-40% of total caloric intake (~1-4 g/kg/day, depending on age), for up to 
5years, including the extension period, with a visit to the clinical siteat day 1, Months 3, 6, 
12, 18, 24,  and annual thereafterfor both groups. Enrolled subjects are otherwise able to 
maintain standard of care treatment which may include anti-epileptic drugs (AEDs) 
throughout the duration of the study.  
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Up to 50 patients with a diagnosis of GLUT1DS who have or have not been previously on 
Triheptanoinwill be enrolledbased on their prior treatment status. 
 
During a two-week screening period, subjects will record daily seizures and diet (last 
threedays) in a diary to serve as a baseline measurement. If a patient has recorded all 
screening criteria prior to consent, that data may be used in lieu of additional screening. If, in 
the opinion of the Investigator, a patient who is currently on the ketogenic dietwould be 
placed at potential risk for compromise of patient safety by stopping ketogenic diet for two 
weeks before initiation of treatment protocol, the two-week screeningperiod from consent to 
initiation may be waived by the Investigator. In the instance of waiving the screening period, 
seizure and diet information will be gathered retrospectively via parent/patient interview. 
After the Screening period, subjects will enter the treatment period on one of two protocol 
schedules. Study Visit window will be +/- 2 weeks from the scheduled date. 
 
5.4.1 Schedule A 
 
 Subjects previously treated with triheptanoin will continue to dose at approximately 
35-40% of total daily calories (~1-4g/kg/day, depending on age).  
 
 The visit schedule will be: Visit 1 (day 1), Visit 2 (13 weeks), Visit 3 (26 weeks), 
Visit 4 (52 weeks), Visit 5 (Year 2, week 26), Visit 6 (Year 2, Week 52), Visit 7 (end 
of Year 3), Visit 8 (end of Year 4), and Visit 9 (end of Year 5), with telephone 
follow-up between visits, as needed.(Table 1) 
 
5.4.2 Schedule B 
 
 Subjects who are naïve to triheptanoin will begin a 2-week fixed titration schedule up 
until they have reached 35-40% of total daily calories (~1-4 g/kg/day depending on 
age).  If a subject has not reached the target of 35-40% of total daily calories, by the 
end of the 2-week fixed titration period, dose titration should continue until achieved 
or until the maximally tolerated dose has been established. 
 
 The visit schedule will be Visit 1 (day 1), Phone Visit (2 weeks), Visit 2(13 weeks), 
Visit 3(26 weeks), Visit 4 (52 weeks), Visit 5 (Year 2, week 26), Visit 6 (Year 2, 
Week 52), Visit 7 (end of Year 3), Visit 8 (end of Year 4), and Visit 9 (end of Year 
5), with telephone follow-up between visits, as needed. (Table 2) 
 
5.4.3 Dose Titration Recommendations 
The table below is a guide for dose titration of a subject to 35-40% of caloric intake 
or the maximum tolerated dose if the maximum dose is <35%. Some discretion and 
flexibility can be used by the Investigator for each subject.  
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Days of Dosing 
Caloric Intake 
If Tolerability Issues Arise: 
Days 1-2 
10% 
N/A 
Days 3-5 
15% 
N/A 
Days 6-8 
20% 
N/A 
Days 9-11 
25% 
Down-titrate to 20% for 3 more days, 
then continue to titrate up if possible.  
Days 12-14 
30% 
Down-titrate to 20% for 3 more days, 
then continue to titrate up if possible. 
Day 15 – study duration 
35-40% 
Down-titrate to 20% for 3 more days, 
then continue to titrate up if possible. 
*Subjects who are unable to tolerate the 35% daily caloric intake will down titrate and re-titrate up to 
determine tolerability. If a subject is still unable to tolerate the 35% caloric intake, the maximum 
tolerated dose as determined by the Investigator will be administered for the duration of the study.  
 
5.4.4 Assessment Schedules 
 
5.4.4.1 Diary 
 
Beginning with the screening visit, subjects or caregivers will record daily seizure 
frequency and diet in the provided diary for 14 days and then during specified 
intervals. As such, subjects will record seizures and diet, as applicable, for 14 days 
post Visit 1 and for 14 days prior to each subsequent study visit. 
 
5.4.4.2 Laboratory 
 
Blood samples will be collected for CBC, Chem-7, ALT/AST, at Screening, Week 
13, and every six months through the end of year 2, and annually thereafter for all 
subjects.  
 
5.4.4.3 Functional Measures 
 
Multiple assessments will be administered at Screening, Months 6 and 12, then once 
per year thereafter during the initial treatment period for all subjects. Those 
assessments are: 
 
 The Vineland Adaptive Behavior Scales  
 The Barry Albright Scales (BAS)* 
 PedsQL  
 Columbia Suicide Severity Rating Scale (C-SSRS)* 
 
*The BAS and C-SSRS are the only functional measures that will be completed during the 
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extension period.  
 
6.0 
OBSERVATIONS AND MEASUREMENTS 
 
6.1 
Vineland Adaptive Behavior Scales, Second Edition (Vineland-II).18 
 
Vineland-II is an assessment designed to evaluate personal and social skills in individuals 
from birth to age 90 with two forms, the survey interview form and the parent/caregiver 
rating form. The two forms are identical except for the mode of administration (either 
interview or rating scale). Eleven general subdomains are grouped into four domains: 
communication, daily living skills, socialization, and motor skills. The four domain 
composite scores then combine to form the adaptive behavior composite for those individuals 
aged birth to 6 years 11 months. Three domain composite scores (communication, daily 
living skills and socialization) combine to form the adaptive behavior composite for those 
aged 7 through 90. Total administration time for the parent/caregiver self-report rating scale 
is approximately 30-60 minutes.   
 
The Vineland-II Parent/Caregiver rating scales were normed on a representative sample of  
3,695 individuals from birth to 90 years. Data for norming and standardization were collected 
on eleven clinical groups: attention deficit/hyperactivity disorder, autism-nonverbal, autism-
verbal, emotional or behavioral disturbance, deafness/hard of hearing, learning disability, 
cognitively delayed-mild (child and adult samples), cognitively delayed-moderate (child and 
adult samples), cognitively delayed severe/profound (adult sample) and visual impairment. 
Extensive analysis of the psychometric properties of the Vineland-II domain, subdomain, and 
adaptive behavior composite scores have been reported and generally reflect good to 
excellent reliability and validity (Sparrow et al., 2005). For instance, split half coefficients 
for the age groups under 3 ranged from .82 to .95 for the Domains and .96 to .98 for the 
Adaptive Behavior Composite; and from .78 to .92 for the Domains and .90 for the Adaptive 
Behavior Composite for children between the ages of 6 months and 2 years, 11 months.  
 
6.2 
Barry-Albright Dystonia Scale (BAS).19 
 
The BAS is a 5-point, criterion-based, ordinal scale designed to assess dystonia in eight body 
regions: eyes, mouth, neck, trunk, upper extremities, and lower extremities. The scale ranges 
from none (0) to severe (4). The maximum total score is 32. Barry, VanSweringen, and 
Albright (1999) utilized 10 patients and 17 raters to assess the psychometric properties of the 
scale. They reported excellent intraclass correlation coefficients (ICC). The reported mean 
ICC scores were as follows:  interrater reliability 0.866, intrarater reliability 0.967 and 0.978, 
and test-retest reliability 0.978 (before training) and 0.967 (after training).  
 
6.3 
The Pediatric Quality of Life Inventory Scale (PedsQL).20 
 
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The PedsQL is a modular approach used to measure the core dimensions of health as defined 
by the World health Organization (WHO) as well as role function. The inventory measures 
health-related quality of life in healthy as well as both acute and chronically ill children. For 
example, the 23-item Generic Core Scale measures across physical (8 items), social (5 
items), school (5 items) and emotional functioning (5 items). It is developmentally age 
specific utilizing a self-report 5-point Likert scale for ages 8 to 18, and a 3-point scale for the 
young child. In addition there is a separate module for parents to report for ages 2 to 4 
(toddler), 5 to 7 (young child), 8 to 12 (child), and 13 to 18 (adolescent) from the care-
giver/parent perspective. It is validated in multi-language form including but not limited to 
English, Spanish and French. 
 
Items are reverse-scored and linearly transformed to a scale of 0 to 100, such that higher 
scores indicate better health related quality of life. Internal consistency reliability alpha 
coefficients for the majority of the child self-report scales and parent proxy-report scales 
exceeded the minimum reliability standard of .70, with the exception of Self-Report School 
Functioning at 0.68. The Total Scale Score (α = 0.88 child, 0.90 parent), Physical Health 
Summary Score (α = 0.80 child, 0.88 parent), and Psychosocial Health Summary Score (α = 
0.83 child, 0.86 parent) were acceptable as well.  
 
One-way ANOVA’s showing differences among chronically ill, acutely ill, and healthy 
children for all scales demonstrated construct validity. Multitrait-multimethod analyses 
revealing correlations with indicators of morbidity and illness burden in the medium to large 
effect size range demonstrated convergent and divergent validity. Factor analysis resulting in 
a five-factor solution for self-report and proxy-report supported the conceptualization of the 
PedsQL as a measurement of an integrated multidimensional construct. 
 
6.4 
Columbia Suicide Severity Rating Scale (C-SSRS)21 
 
The US FDA has recommended the use of the C-CASA as a standardized suicidal rating 
system for anticonvulsant trials and other centrally acting agents and nonpsychotropic drugs. 
 
The C-SSRS is a suicidality rating scale that is used extensively across primary care, clinical 
practice, surveillance, research and institutional settings. It is available in 103 languages and 
maps to the Columbia Classification Algorithm for Suicide Assessment (C-CASA). The C-
SSRS was designed todistinguish the domains of suicidal ideation and suicidalbehavior using 
four constructs: severity of ideation, intensity of ideation, behavior, and lethality. Severity of 
ideation is rated on a 5-point scale with 1 being “wish to be dead”, 2 “nonspecific active 
suicidal thoughts”, 3 “suicidal thoughts with methods”, 4 “suicidal intent”, and 5 “suicidal 
intent with plan”. The intensity of ideation subscale comprises 5 items, each rated on a 5-
point scale: frequency, duration, controllability, deterrents, and reason for ideation. The 
behavior subscaleis rated as actual, aborted, and interrupted attempts; preparatory behavior; 
and nonsuicidal self-injurious behavior. The lethality subscale assesses actual attempts and is 
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rated on a 6-point scale. If actual lethality is zero, potential lethality of attempts is rated on a 
3-point scale.The C-SSRS has demonstrated good convergent and divergent validity with 
other multi-informant suicidal ideation and behavior scales. It ishighly sensitive and specific 
for suicidal behavior classifications. Both the ideation and behavior subscales were sensitive 
to change over time. The intensity of ideation subscale demonstrated moderate to strong 
internal consistency 
 
The C-SSRS uses different assessment periods, dependingon research or clinical need; the 
lifetime period assessesthe worst-point ideation, which research has suggestedmay be a 
stronger predictor of subsequent suicide thancurrent ideation. The following versions will be 
used in this study: (1) baseline, (2) since last visit, (3) pediatric baseline, (4) pediatric since 
last visit. 
 
Assessments will be administered for subjects ten years of age and older.  
 
6.5 Tracking Diary 
 
6.5.1 Seizures 
 
A seizure diary will be used to track date, type, number, and unusual presentation of seizures. 
Subjects will be given a seizure diary at screening to record daily seizure activity for 
incremental periods of time. They will be instructed to record date and answer the question 
“Did you/your child experience any seizures today?” An affirmative answer requires 
completion of the form; a negative answer does not. Regardless of whether a subject 
experienced a seizure, additional medications administered and not previously recorded will 
be reported on this daily form. Subjects will describe activity during and post seizure. They 
will also record the type or description and number of other seizures that occurred that day. 
 
Subjects will complete this form daily during the screening period. They will return the 
completed diary to the research team at Visit 1. Subjects will then receive a new seizure 
diary. Subjects will track daily seizures for two weeks following Visit one and then for two 
weeks prior to each subsequent study visit. Subjects will return the completed diary and 
receive a new diary at each visit. 
 
6.5.2  Diet 
 
A diet diary will be used to track daily food consumption. Subjects will record the time of 
consumption, type of food or beverage, amount eaten, place eaten, and individuals present at 
time of consumption. This should be completed for each of the three days prior to a study 
visit. The form is incorporated into the seizure diary. Thus, a grid entitled Diet Diary is 
located below the seizure diary for each of the final days before a study visit.  
 
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7.0 
CRITERIA FOR EVALUATION 
 
7.1 
Safety 
 
Safety events and tolerability will be recorded as adverse events (AE) or serious 
adverse events (SAE) except for those events that are related to GLUT1 
deficiency such as epileptic seizures or abnormal movements. 
 
Physical examination, weight, vital signs, and laboratory tests will be conducted 
periodically 
 
7.2 
Safety Monitoring 
 
Triheptanoin adverse drug reactions include GI disturbance and weight gain.  
Monitoring of these and other potential AEs will occur during study visits and 
telephone calls throughout the study, as needed.  Consultation with a dietician will 
be utilized as needed.   
 
7.3 
Efficacy 
 
Seizure frequency:  The number of observable seizures will be recorded once per 
day, via diary by patient or caregiver  
 
8.0 
CRITERIA FOR REMOVAL OF SUBJECTS FROM THERAPY OR 
ASSESSMENT 
 
Subjects may be removed from the study for the following reasons: 
 
1. Occurrence of an adverse event (AE), a collection of unassociated AE, or a pattern of 
AE which in the judgment of the Medical Monitor, make further participation in the 
trial an unacceptable risk of harm to the subject  
2. An illness that, in the judgment of the Medical Monitor, might place the subject at 
risk 
3. At the request of the subject or PI 
4. In the judgment of the PI, an unacceptable number or seriousness of  protocol 
deviations or unreliable behavior on the part of the subject 
 
9.0 
POTENTIAL RISKS AND POTENTIAL BENEFITS 
 
Triheptanoin has been used clinically for over a decade in human studies and is currently 
being developed in a number of different diseases.  Approximately 130 subjects with various 
disorders, including 65 FAOD subjects (ranging from neonates to adults), have been treated 
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with triheptanoin  for periods up to 13 years with evidence of clinical benefit and no 
significant safety issues reported.  
 
Data from nonclinical and clinical studies to date suggest triheptanoin does not pose any 
significant safety risks that can be identified at this time. Triheptanoin has been well tolerated 
in humans with no significant safety issues and toxicology or adverse pharmacology findings 
were not observed in triheptanoin -treated animals.  Studies in animals and humans suggest 
triheptanoin consumed orally has side effects that are similar to those of orally consumed 
medium chain triglycerides.  The most commonly reported adverse effects are 
gastrointestinal distress and excessive weight gain at high doses.  Both of these issues appear 
to resolve when subjects consume triheptanoin in small doses mixed with foods throughout 
the day and when total caloric intake is appropriately managed. 
 
Overall, the risk-benefit ratio of triheptanoin  for GLUT1 DS appears to be favorable based 
on the safety record to date, the efficacy of triheptanoin in animal models of seizure, the 
mechanism of action of triheptanoin  in providing energy and anaplerotic substrates to the 
brain, and the significant unmet medical need of GLUT1 DS. 
 
 
10.0 
DATA COLLECTION AND ADVERSE EXPERIENCE REPORTING 
 
10.1 
Clinical Data Collection 
 
Data to be collected will include demographic features (gender, age, ethnicity and race), 
GLUT1 DS medical history, prior and concomitant medications and therapies, details of the 
3-day diet record and seizure count from the daily patient diary, and results obtained at each 
office visit (weight, height, vitals, physical examination, and labs). In addition, data will be 
collected on adverse events. The entire list of variables and explanations can be found in the 
Data Dictionary.  
 
10.2 
Data Management 
 
Data Management will be provided by Cook Children’s Health Care System Research 
Administration Office (CCHCS RAO) and includes forms design, development of an 
electronic case report form (eCRF), collecting, managing, editing, storing, and reporting on 
data; as well as, training and access to the data for the study statistician. 
The eCRF’s will be maintained and updated by CCHCS RAO to reflect the changes within 
the protocol. This database will be converted to a REDCap database at such time as that 
platform is fully implemented within the CCHCS RAO.  
 
10.3 
Data Storage 
 
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Data will be stored in an electronic database created by CCHS RAO. The database will be 
password protected and identifiable information will be kept in the database. The database 
will be maintained on CCHCS servers. Only individuals listed as key study personnel 
approved by the IRB will have direct access to the database. Any written study-related 
records will be maintained for at least 3 years following the completion of the study; then 
destroyed using a cross-cut shredder. Electronic study-related records and results will only be 
kept in aggregate form following completion of the study. 
 
10.4 
Procedures to Maintain Confidentiality 
 
To minimize the chance of harm associated with PHI and identifiable study data collection, 
all information abstracted from the electronic medical record will be stored in a password-
protected database maintained on CCHCS servers by study staff.  To maintain 
confidentiality, all patient identifiers will be removed prior to disclosure; any disclosed data 
will be for scientific abstract and publication to the medical community. Consent and assent 
forms will locked in the research administration office.  
 
10.5 
Quality Assurance 
 
10.5.1 Edit checks and query resolution 
 
Data entered into the eCRF will subjected to auto-validation (ranges, data checks) and edits 
on a “real time” basis as well as batch edits. The batch edits will query inconsistent 
responses, missing forms, missing data, and data anomalies. The Data Manager will review 
each discrepancy report. Resolved queries will then be incorporated into the database. 
 
10.5.2  Audit trail 
 
An electronic audit trail of all changes is maintained by the system (i.e., by recording the 
change, name of user making the change, date/time). 
 
10.5.3  Site monitoring 
 
Site monitoring will be completed by a Cook Children’s Health Care System representative 
on an internal basis.The functions of internal monitoring include the review of timeliness of 
provision of data, the collection of initial and updated regulatory documents, and frequency 
of identified and resolved issues. 
 
10.6  Adverse Event Reporting 
 
10.6.1 Safety monitoring 
 
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Safety monitoring includes the systematic review of clinical laboratory results and 
measurement data for trends that may impact patient safety. The processing, reviewing, and 
reporting of adverse experiences and serious AE are also captured.  
 
 A serious adverse event (SAE) is defined as: Death, or immediately life-threatening, 
or permanently [or significantly] disabling, or requiring hospitalization, or 
prolongation of hospitalization, or a congenital anomaly. Elective planned 
hospitalizations, unrelated to either the disease being studied or the study (e.g., for 
tonsillectomy), will not be considered serious adverse events.  
 
 An unexpected adverse event is one that is not identified in nature, severity or 
frequency as described in for these AEDs.  
 
10.6.2 Medical Safety Monitor 
 
All SAEs will be reported per local IRB policy. This study will utilize a medical safety 
monitor named in the Independent Medical Monitoring Charter. The Medical Safety Monitor 
will provide the medical coverage needed when serious or unexpected AEs occur.  
 
10.6.3 Stopping Rules  
 
The Medical Safety Monitor will act in an advisory capacity to monitor the safety of subjects 
on a routine basis throughout the trial. The drug safety and pharmacovigilance group at 
Ultragenyx will review SAEs and may provide advice in any determination of whether study 
enrollment should be paused or if the study should be halted. 
 
Individual subjects who experience any unexpected and possibly, probably, or definitely 
drug-related SAEs that represent a change in the nature or an increase in frequency of the 
serious event from their prior medical history will be assessed as to whether the subject will 
continue on the study. 
 
Should unexpected and possibly, probably, or definitely drug-related SAEs occur, a full 
clinical evaluation will be performed by the medical safety monitor, the principal 
investigator, and drug safety and pharmacovigilance group in order to make a decision 
regarding what actions to take, including whether to recommend stopping the study and 
informing the IRB. 
 
 
10.6.4  Safety Report 
 
Copies of all reports will be stored in the Study File. All SAEs will be reported to the FDA, 
the CCHCS IRB, and the supporting institution, Ultragenyx, Inc.  
 
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10.6.4  Protocol Violations  
 
Protocol violations are events that are inconsistent with the protocol to the extent of 
impacting the study outcome and / or GCP guidelines. Protocol violations include but are not 
limited to violations regarding consent and IRB issues, administration of wrong treatment 
and incorrect laboratory testing. Protocol violations should be reported per the CCHCS RAO 
policy. 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Safety Analysis 
 
Safety data will be reviewed annually or more frequently, as needed, by another physician 
investigator familiar with the disorder and treatment. For the safety analysis, the numbers 
(frequency) and incidence rates of AEs and SAEs will be summarized during exposure to 
triheptanoin throughout the study. The analyses of safety will include all subjects who 
receive any triheptanoin during the study and provide any post-treatment safety information. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The incidence and frequency of AEs will be summarized by System Organ Class (SOC), 
Preferred Term (PT), relationship to study drug, and severity. A by-subject listing will be 
provided for those subjects who experience a SAE, including death, or experience an AE 
associated with early withdrawal from the study or study drug treatment. 
 
Clinical laboratory data will be summarized by the type of laboratory test. The frequency and 
percentage of subjects who experience abnormal clinical laboratory results (i.e., outside of 
reference ranges) and/or clinically significant abnormalities after study drug administration 
will be presented for each clinical laboratory measurement. For each clinical laboratory 
measurement, descriptive statistics will be provided for Baseline and all subsequent 
scheduled visits during which laboratory measurements were obtained. Changes from 
Baseline to the treatment visits will also be provided. Descriptive statistics of vital signs and 
concomitant medications will be provided in a similar manner. 
 
11.2 
Efficacy Analysis 
 
For efficacy analysis, seizure frequency expressed as the number per month will be 
calculated during treatment and compared to the historical seizure rate prior to treatment with 
triheptanoin. Change from baseline will be expressed as median percent reduction in baseline 
seizure frequency.   
 
12.0 
 HUMAN SUBJECTS  
 
12.1  Institutional Review Board (IRB) Review and Informed Consent  
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This protocol and the informed consent/assent documents and any subsequent modifications 
will be reviewed and approved by the CCHCS IRB. A signed consent form will be obtained 
from the LARfor each enrolled subject as described in detail in section 5.3. 
 
12.2 
 Study Modification/Discontinuation  
 
The study may be modified or discontinued at any time by the Cook Children’s IRB, the 
sponsor, the OHRP, the FDA, or other government agencies as part of their duties to ensure 
that research subjects are protected.  
 
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TABLE 1: SCHEDULE OF EVENTS– SUBJECTS PREVIOUSLY ON AND CONTINUING ON TRIHEPTANOIN 
 
Screening 
Initial Treatment 
Extension 
End of 
Study or 
Termination 
Name of Visit 
Screening Visit 
Visit 1 
Visit 2, 3 
Visits 4-6 
Visits 7-8 
Visit 9 
Timepoint 
-14 days 
Day 1 
Week 13, 
26 
Every 6 
mos 
Annually 
Annually 
Informed Consent 
a) LAR 
b) Assent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
GLUT1 DS Medical History 
X1 
 
 
 
 
 
 
Prior and Concomitant Medications 
& Therapies 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Dietician Consult2 
(including 3-day diet record review) 
 
X 
X 
X 
X 
X 
X 
Daily Patient Diary Review:  Seizure 
Count  
X 
X 
X 
X 
X 
X 
X 
Weight and vitals3 
X 
X 
X 
X 
X 
X 
X 
Physical Examination4 
X 
X 
X 
X 
X 
X 
X 
Labs 
a) CBC5 
b) Chemistry6 
X 
 
X 
X 
X 
X 
X 
Vineland Adaptive Behavior Scales 
(Vineland-II) 
X  
 
X 
X 
X 
 
X 
Barry Albright Scale 
X 
 
X 
X 
X 
X 
X 
PedsQL 
X 
 
X 
X 
X 
 
X 
Columbia Suicide Severity Rating 
Scale (C-SSRS) 
X 
X 
X 
X 
X 
X 
X 
Urinalysis: dipstick 
To test for pregnancy in females of 
child-bearing potential 
X 
X 
X 
 
 
 
 
 
IRB NUMBER: 2013-034
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TABLE 2: SCHEDULE OF EVENTS – SUBJECTS NAÏVE TO TRIHEPTANOIN 
 
Screening 
Initial Treatment 
Extension  
End of 
Study or 
Termination 
Name of Visit 
Screening 
Visit 
Visit 1 
Phone 
Visit 
Visit 2, 3 
Visits 4-6 
Visits 7-8 
Visit 9 
Timepoint 
-14 days 
Day 1 
Day 14 
Week 13, 
26 
Every 6 
mos 
Annually 
Annually 
Informed Consent 
c) LAR 
d) Assent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
GLUT1 DS Medical History 
X7 
 
 
 
 
 
 
 
Prior and Concomitant 
Medications & Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Dietician Consult8 
(including 3-day diet record 
review) 
 
X 
 
X 
X 
X 
X 
X 
Daily Patient Diary Review:  
Seizure Count  
X 
X 
X9 
X 
X 
X 
X 
X 
Weight and vitals10 
X 
X 
 
X 
X 
X 
X 
X 
Physical Examination11 
X 
X 
 
X 
X 
X 
X 
X 
Labs 
c) CBC12 
d) Chemistry13 
X 
 
 
X 
X 
X 
X 
X 
Vineland Adaptive Behavior 
Scales (Vineland-II) 
X  
 
 
X 
X 
X 
 
X 
Barry Albright Scale 
X 
 
 
X 
X 
X 
X 
X 
PedsQL 
X 
 
 
X 
X 
X 
 
X 
Columbia Suicide Severity 
Rating Scale (C-SSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis: dipstick 
To test for pregnancy in females 
of child-bearing potential 
X 
X 
 
X 
 
 
 
 
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Subjects currently or previously treated with triheptanoin 
1 GLUT1-DS History, patients must have been confirmed via historical test or by physician diagnosis 
2 Three-day diet diaries are to be reviewed with the dietician or study staff upon each indicated visit. 
3 Weight (kg). Vitals includes blood pressure (mm Hg),  heart rate in beats per minute, respiration rate in breaths per minute and temperature in 
degrees Celsius (°C), and should be performed at the beginning of each visit before additional assessments are completed. 
4 Physical Examination: HEENT, neck, respiratory-auscultation of lungs. 
5 CBC panel: Hematocrit, hemoglobin, platelet, RBC, WBC. 
6 Chemistry panel:sodium, potassium, chloride, bicarbonate or CO2, blood urea nitrogen (BUN), creatinine, glucose, ALP, ALT (or SGPT), AST 
(or SGOT), total bilirubin, GGT, albumin, total protein, calcium. 
 
Subjects currently or previously treated with triheptanoin 
7 GLUT1-DS History, patients must have been confirmed via historical test or by physician diagnosis 
2 Three-day diet diaries are to be reviewed with the dietician or study staff upon each indicated visit. 
9Discuss continued completion of seizure diary.  
10 Weight (kg). Vitals includes blood pressure (mm Hg),  heart rate in beats per minute, respiration rate in breaths per minute and temperature in 
degrees Celsius (°C), and should be performed at the beginning of each visit before additional assessments are completed. 
11 Physical Examination: HEENT, neck, respiratory-auscultation of lungs. 
12 CBC panel: Hematocrit, hemoglobin, platelet, RBC, WBC. 
13 Chemistry panel:sodium, potassium, chloride, bicarbonate or CO2, blood urea nitrogen (BUN), creatinine, glucose, ALP, ALT (or SGPT), AST 
(or SGOT), total bilirubin, GGT, albumin, total protein, calcium. 
 
IRB NUMBER: 2013-034
IRB APPROVAL DATE: 04/04/2019
IRB EXPIRATION DATE: 04/03/2020


Protocol Number:  2013-NEUR-001 
Version: 4.0 
10-Jan-2018 
 
 
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REFERENCES 
 
1. Pearson T, Akman C, Hinton V, Engelstad K, De Vivo D. Phenotypic spectrum of 
glucose transporter type 1 deficiency syndrome (Glut1 DS). Curr Neurol Neurosci Rep. 
April 2013;13(4):342.  
2. Pong A, Geary B, Engelstad K, Natarajan A, Yang H, De Vivo D. Glucose transporter 
type I deficiency syndrome: epilepsy phenotypes and outcomes. Epilepsia. 
2012;53(9):1503-1510.  
3. Johnson W. Final report on the safety assessment of trilaurin, triarachidin, tribehenin, 
tricaprin, tricaprylin, trierucin, triheptanoin, triheptylundecanoin, triisononanoin, 
triisopalmitin, triisostearin, trilinolein, trimyristin, trioctanoin, triolein, tripalmitin, 
tripalmitolein, triricinolein, tristearin, triundecanoin, glyceryl triacetyl hydroxystearate, 
glyceryl triacetyl ricinoleate, and glyceryl stearate diacetate. Int J Toxicol. 2001;20 Suppl 
4:61-94.  
4. Roe CR. Inherited disorders of mitochondrial fatty acid oxidation: a new responsibility 
for the neonatologist. Semin Neonatol. 2002;7:37-47. 
5. Kinman R, Kasumov T, Brunengraber H, et al. Parenteral and enteral metabolism of 
anaplerotic triheptanoin in normal rats. Am J Physiol Endocrinol Metab. 
2006;291(4):E860-E866.  
6. Deng S, Zhang G, Kasumov T, Roe C, Brunengraber H. Interrelations between C4 
ketogenesis, C5 ketogenesis, and anaplerosis in the perfused rat liver. J Biol Chem. 
2009;284(41):27799-27807.  
7. Gu L, Zhang G, Brunengraber H, et al. Parenteral and enteral metabolism of anaplerotic 
triheptanoin in normal rats. II. Effects on lipolysis, glucose production, and liver acyl-
CoA profile. Am J Physiol Endocrinol Metab. 2010;298(2):E362-E371.  
8. Marin-Valencia I, Good L, Ma Q, Malloy C, Pascual J. Heptanoate as a neural fuel: 
energetic and neurotransmitter precursors in normal and glucose transporter I-deficient 
(G1D) brain. J Cerebr Blood F Met. 2013;33(2):175-182.  
9. Willis S, Stoll J, Sweetman L, Borges K. Anticonvulsant effects of a triheptanoin diet in 
two mouse chronic seizure models. Neurobiol Dis. 2010;40(3):565–572. 
10. Thomas N, Willis S, Sweetman L, Borges K. Triheptanoin in acute mouse seizure 
models. Epilepsy Res. 2012;99(3):312-317.  
11. Kim T, Borges K, Petrou S, Reid C. Triheptanoin reduces seizure susceptibility in a 
syndrome-specific mouse model of generalized epilepsy. Epilepsy Res. 2013;103(1):101-
105.  
12. Ataíde TdaR, de Olivera SK, da Silva FM, Vitorino Filha LGC, do N Tavares MC, 
Sant’Ana  AEG. Toxicological analysis of the chronic consumption of diheptanoin and 
triheptanoin in rats. Intl J Food Sci Tech. 2009;44:484-492. 
13. Roe C, Sweetman L, Roe D, David F, Brunengraber H. Treatment of cardiomyopathy and 
rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain 
triglyceride. J Clin Invest. 2002;110(2):259-269.  
14. Roe C, Mochel F. Anaplerotic diet therapy in inherited metabolic disease: therapeutic 
potential. J Inherit Metab Dis. 2006;29(2-3):332-340.  
15. Mochel F, Duteil S, Durr A, et al. Dietary anaplerotic therapy improves peripheral tissue 
energy metabolism in patients with Huntington's disease. Eur J Human Genet. 
IRB NUMBER: 2013-034
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IRB EXPIRATION DATE: 04/03/2020


Protocol Number:  2013-NEUR-001 
Version: 4.0 
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Confidential 
 Page 27 of 27 
 
 
 
2010;18(9):1057-1060.  
16. Baruteau J, Sachs P, Ogier de Baulny H, et al. Clinical and biological features at 
diagnosis in mitochondrial fatty acid beta-oxidation defects: a French pediatric study of 
187 patients. J Inherit Metab Dis. October 3, 2012 
17. Goldstein A, Barone AR, DeWard SJ, Payne N, Vockley J. Triheptanoin therapy for 
inherited disorders of fatty acid oxidation. Mitochondrion. 2012;12(5):566. 
18. Sparrow, SS, Cicchetti D, & Balla DA. Vineland Adaptive Behavior Scales - 2nd Edition 
manual. Minneapolis, MN: NCS Pearson, Inc; 2005. 
19. Barry M, VanSwearingen J, Albright A. Reliability and responsiveness of the Barry-
Albright Dystonia Scale. Dev Med Child Neurol. 1999;41(6):404-411.  
20. Varni J, Burwinkle T, Seid M. The PedsQL as a pediatric patient-reported outcome: 
reliability and validity of the PedsQL Measurement Model in 25,000 children. Expert Rev 
Pharmacoecon Outcomes Res. 2005;5(6):705-719. 
21. Posner K, Brown GK, Stanley B, Brent DA, et al.The Columbia- Suicide Severity Rating 
Scale (C-SSRS): initial validity and internal consistency findings from three multi-site 
studies with adolescents and adults.American Journal of Psychiatry. 2011; 168:1266-
1277.  
 
IRB NUMBER: 2013-034
IRB APPROVAL DATE: 04/04/2019
IRB EXPIRATION DATE: 04/03/2020