Compatibility of Triheptanoin (C7) With the Ketogenic Diet in Patients Diagnosed With Glucose Transporter Type 1 Deficiency
Phase: PHASE2
Conditions: GLUT1DS1
Sponsor: University of Texas Southwestern Medical Center

STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
Official title: Compatibility of triheptanoin (C7) with the 
Ketogenic Diet in Patients Diagnosed with Glucose 
Transporter Type 1 Deficiency (G1D) 
 
 
 
NCT number:  NCT03301532 
IRB Approved date: 01-22-2021 

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PROTOCOL TITLE: 
Compatibility of triheptanoin (C7) with the Ketogenic  
 
Diet in Patients Diagnosed with Glucose Transporter 
Type 1 Deficiency (G1D)  
 
Protocol Number: 
Protocol 3 
 
Protocol Date:                  January 21, 2021 
 
Version:  
 
      7 
 
Investigator: 
Juan M. Pascual, MD, PhD 
Director, Rare Brain Disorders Program 
Departments of Neurology and Neurotherapeutics, Physiology and Pediatrics, and 
Eugene McDermott Center for Human Growth & Development / Center for Human 
Genetics 
UT Southwestern Medical Center, Dallas, Texas 
Children’s Medical Center, Dallas, Texas 
 
Sponsor: National Institutes of Neurological Disorders and Stroke (NINDS) 
 
Trial Site Contact Information: 
Children’s Medical Center 
Dallas Ambulatory Care Pavilion 
2350 Stemmons Freeway (I-35) 
Dallas, Texas 75207 
Tel. (214) 456-2768 
 
Clinical Laboratories: 
Jason Park, MD, PhD 
Director, Advanced Diagnostics Laboratory, Children’s Medical Center 
Assistant Professor, Pathology and Eugene McDermott Center for Human Growth & 
Development 
UT Southwestern Medical Center 
1935 Medical District Drive 
Dallas, Texas 75235 
Tel. (214) 456-2320 

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TABLE OF CONTENTS 
 
 
 
Page 
 
SYNOPSIS ..………………………………………………………………………………. 
4 
 
1. 
STUDY OBJECTIVES …………………………………………………………... 
4 
 
1.1 
Primary Objectives……………………………………………….………….. 
4 
 
2. 
BACKGROUND ……………………………………………………………...….. 
5 
 
2.1 
Rationale ...…………………………………………………………………..… 
5 
2.2 
Supporting Data ……………………………….……………………………… 
6 
 
3. 
STUDY DESIGN ……………………………………………………...………….. 7 
 
4. 
SELECTION AND ENROLLMENT OF SUBJECTS ……………...…………. 
7 
 
4.1 
Inclusion Criteria ……………………………………………………..……….. 
7 
4.2 
Exclusion Criteria ………………………………………………………..……. 
7 
4.3 
Study Enrollment Procedures ……………………………………….………. 
8 
 
5. 
STUDY INTERVENTIONS …………………………………………….…………. 11 
 
5.1 
Interventions, Administration, and Duration ……………………….………..   11 
5.2 
Handling of Study Interventions …………………………………….………… 12 
5.3 
Concomitant Interventions ……………………………………………….……. 12 
5.4 
Adherence Assessment ………………………………………………………... 13 
 
6. 
CLINICAL AND LABORATORY EVALUATIONS …………………………….  14 
 
6.1 
Schedule of Evaluations …………………………………………….…………. 14 
6.2 
Timing of Evaluations …………………………………………………….…….  14 
6.3 
Special Instructions and Definitions of Evaluations ……………….………..  16 
 
7. 
MANAGEMENT OF ADVERSE EXPERIENCES ...……………………...……. 18 
 
8. 
CRITERIA FOR INTERVENTION DISCONTINUATION ……………...……….18 
 
9. 
STATISTICAL CONSIDERATIONS ……………………………………...…….. 19 
 
9.1 
General Design Issues ………………………………………………..………... 19 
9.2 
Outcomes ………………………………………………………………...………19 

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Page 
 
9.3 
Sample Size and Accrual …………………………………………..…………  20 
9.4 
Data Monitoring ………………………………………………………..……....  20 
9.5 
Data Analyses …………………………………………………………...……..  21 
 
10. 
DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE 
REPORTING ……………………………………………………………………... 21 
 
10.1 Records to be Kept ………………………………………………………..…… 21 
10.2 Role of Data Management ………………………………………………..…… 23 
10.3 Quality Assurance …………………………………………………………...… 23 
10.4 Adverse Experience Reporting ……………………………………………..…. 24 
 
11. 
HUMAN SUBJECTS ……………………………………………………..…….   27 
 
11.1 Institutional Review Board (IRB) Review and Informed Consent …...…..     27 
11.2 Subject Confidentiality …………………………………………………..…….   27 
11.3 Study Modification/Discontinuation ………………………………….…..…… 27 
 
12. 
ETHICAL CONSIDERATIONS…………………………………………………. 28 
 
12.1 Risk/Benefit Assessment……………………………………………………….. 28 
12.2 Pediatric Populations…………………………………………………………… 28 
 
13. 
PUBLICATION OF RESEARCH FINDINGS …………………………...…….. 28 
 
14. 
REFERENCES ………………………………………………………...………..  29 
 
 
 
 
 

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SYNOPSIS 
 
Study Title 
Compatibility of triheptanoin (C7) with the Ketogenic Diet in Patients Diagnosed with 
Glucose Transporter Type 1 Deficiency (G1D) 
Objectives 
Primary Objectives: To explore triheptanoin (C7 oil; C7) compatibility with the ketogenic 
diet by evaluating EEG (for the determination of outcome EEG as defined below), and 
seizure rate, glycemia and ketosis in proven G1D patients receiving (both prior to en- 
rolment and for the duration of this study) a ketogenic diet. 
 
Secondary Objectives: N/A 
Design and Outcomes 
This is a single-site, open-label proof of principle exploratory trial to investigate the 
compatibility of C7 oil with the ketogenic diet in subjects genetically diagnosed with G1D. 
The primary outcome measure is change in EEG during C7 supplementation. The sec- 
ondary outcome measures are: changes in seizure rate, glycemia (blood glucose lev- els), 
and ketosis (beta-hydroxybutyrate levels). 
 
Interventions and Duration 
 
This is an open-label, single arm proof of principle trial of orally-administered C7 in sub- 
jects diagnosed with G1D and currently receiving (i.e., prior to enrolment) a ketogenic 
diet. The ketogenic diet will have been previously prescribed by the patient’s treating 
physician independently of this study and for clinical reasons (i.e., the treatment of G1D 
epilepsy). Because the ketogenic diet supplies well over 50% of calories from fat, 
subjects, who are already tolerating over this much fat as part of their previously- 
prescribed ketogenic diet, will replace 45% of their daily caloric intake with C7 for 
24 hours, during a 48 hour inpatient stay. During observation, subjects will have contin- 
uous EEG to monitor for any potential C7-related changes in seizure activity before, 
during, and after C7 ingestion. Subjects will undergo clinical evaluation and comprehen- 
sive blood work at baseline and discharge, and continuous EEG and evaluation of glu- 
cose and beta-hydroxybutyrate levels while inpatient and receiving C7. Total time of 
participation is 4 days. 
 
Sample Size and Population 
 
Fifteen subjects receiving ketogenic diet and with a known (genetically determined) 
G1D diagnosis will be enrolled. Subjects may be male or female, between the ages of 
2.5 and 35 years 11 months old (N=5 per age group: 2.5 to 6, 7-11, and 12-35 years 11 
months), and must be willing to provide assent if they are of age (age 10-17). Subjects 
may be English or Spanish speaking. Subjects may be currently taking anticonvulsants or 
other medications. Because of potential C7- supplemental dietary medium chain tri- 
glyceride interference, subjects may not have had medium chain triglyceride dietary 

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supplements in the past 24 hours and must agree not to consume additional supple- 
mental medium chain triglyceride while on this trial. In practice, subjects will replace any 
supplemental medium chain triglyceride with any other fat that they are currently con- 
suming. 
 
1.  STUDY OBJECTIVES 
 
1.1. 
The main hypotheses tested are: 
 
• C7 metabolism will not interfere with previously-acquired ketosis in G1D, as 
measured by no change in EEG from pre-C7 baseline. 
• C7 metabolism will not interfere with previously-acquired ketosis in G1D, as 
measured by no increase in observable seizure rate and no clinically relevant 
changes glycemia and ketosis, as measured by random glucose levels and 
beta-hydroxybutyrate levels. 
 
 
 
2.  BACKGROUND 
 
2.1. 
Rationale 
 
Glucose transporter deficiency type 1 (G1D), a prototypic glycolytic defect that 
impairs the first step of glucose metabolism, was first described in 1991 and is 
caused by haploinsufficiency of the blood brain barrier and astrocyte glucose 
transporter (1-3). In its most common form, G1D leads to epilepsy and intellectual 
discapacity. Associated features include microcephaly (signifying limited brain 
growth) and movement incoordination (ataxia). There is no alteration of systemic 
carbohydrate metabolism. 
 
Some manifestations of G1D are treatable in a significant fraction of patients: In 
~2/3 of over 100 subjects that we have cared for over the years, a ketogenic diet 
has been efficacious for seizure control but without significantly impacting intel- 
lectual discapacity or ataxia ((4) and PI observations). Therefore, G1D is at least 
partially responsive to the alternative fuels generated by the diet in a fraction of 
patients, namely even-carbon-number fatty acids and ketone bodies (2). We cur- 
rently care for over 100 G1D genetically-confirmed subjects, representing ~40% of 
all North American and ~10% of European subjects either reported or genotyped 
(often by us (5) under our NIH CETT Program for G1D) and we have elucidated 
the principal brain metabolic pathways in G1D (6). Although much work remains to 
be carried out to fully understand the biochemistry of the disorder, significant 
progress has been made in G1D, such that we believe that the finding of enhanced 
anaplerosis after administration of the C7 constituent heptanoate and related 
indicators of tricarboxylic acid (TCA) cycle stimulation (7) warrants 
the trial of anaplerotic therapy at this time in this disease. An additional sense of 
urgency is imposed by the potential window of opportunity that closes once the 
child brain matures. 
 
Because heptanoate metabolism generates acetyl-CoA, C7 can potentially stimu- 

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late hepatic neoglucogenesis and this can decrease ketosis via insulin release 
(113). Neoglucogenesis stemming from heptanoate was observed by us after in- 
fusion of heptanoate in G1D mice (28). However, the relative amount of hep- 
tanoate infused was far greater than that used for G1D subjects. This was 
expected because a large quantity of labeled substrate is necessary to achieve 
labeling of brain intermediary metabolites in human and mouse 13C NMR experi- 
ments as developed by us (27, 32, 114, 115). Thus, no significant neoglucogen- 
esis (i.e., an increase in glycemia >10 mg/dl) is obligatorily anticipated after C7 
ingestion. 
 
Preliminary studies. One G1D subject has received C7 at 45% while on a 3.5:1 
ketogenic diet without clinical or analytical consequence. Our 14 G1D subjects on 
a regular diet studied in the fasting state (8) exhibited a mean blood glucose of 
88.5±1.9 mg/dl (mean ± SEM), which did not significantly change 30-60 min after 
ingestion of the base dose (35%) of C7 (87.8±2.4 mg/dl). Beta- hydroxybutyrate 
levels were also unchanged (0.25±0.10 mM in the fasting state relative to 0.23±0.1 
mM in the post-C7 state; mean±SEM). The same conclusion was reached after 10 
of these subjects were tested after 3 months on C7. Thus, C7 metabolism does 
not appreciably interfere with glucose metabolism and related ketosis (beta-
hydroxybutyrate) under a regular diet. 
 
Fifteen subjects with G1D (five per each of three age groups) and currently re- 
ceiving a ketogenic diet will participate. After baseline measurements of common 
blood analytes, EEG, and blood ketone body levels, subjects will be given trihep- 
tanoin dosed by individual daily caloric intake, divided in 4 daily fractionated dos- 
es. 
All subjects will take triheptanoin for 24 hours (4 doses) on an inpatient basis. 
This study, if the hypothesis is correct, will enable future combined or compara- 
tive studies because, for 1/3 of G1D patients, the ketogenic diet is insufficient and 
may be supplemented with C7 or replaced by it depending on future work, 
whereas, conversely, C7 may prove insufficient as first line therapy in some pa- 
tients and necessitate the addition of a ketogenic diet. 
 
2.2 Supporting Data 
 
There is evidence of beneficial effects of C7 metabolism on the TCA cycle G1D 
(7). This evidence stems from work in the G1D mouse model via 13C nuclear 
magnetic resonance (NMR) spectroscopy and mass spectrometry. Open-label 
treatment using triheptanoin has been pioneered by us in several disorders char- 
acterized by impaired anaplerosis (9-12), proving safe, tolerable and efficacious. 
 
The dosing, tolerability, and safety profile of triheptanoin has been documented in other 
disorders (9-12). Therapeutic response is seen at approximately 35% of the daily caloric 
needs supplied by C7 oil, and 14 years of experience administering C7 has elicited no 
serious adverse events. However, side effects of mild stomach upset, nausea, and mild 
weight gain have been observed. Because C7 oil is a fat, it is possible that subjects will 

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experience changes in lipid levels, cholesterol, and triglycerides, but these changes have 
not been observed. 
 
3.  STUDY DESIGN 
 
 
This is an open-label, proof of principle trial of C7 in subjects with G1D and cur- 
rently on ketogenic diet. 
 
Fifteen subjects with G1D receiving ketogenic diet will be enrolled. Subjects will 
undergo baseline and exit clinic procedures in the Neurology Outpatient Clinic lo- 
cated in the Children’s Medical Center Ambulatory Care Pavilion. Inpatient pro- 
cedures including blood draws will be completed in the Children’s Medical Center 
Epilepsy Monitoring Unit (EMU). These facilities can accommodate both pediatric 
and adult patients. 
 
Evaluation of EEG will be accomplished at the pre- and post-C7 assessments. 
Evaluation of random glucose and beta-hydroxybutyrate levels will be accom- 
plished at the baseline, 4 on-treatment, and exit assessments. 
 
 
 
4.  SELECTION AND ENROLLMENT OF SUBJECTS 
 
4.1. 
Inclusion Criteria 
 
4.1.1. Diagnosis of glucose transporter type I deficiency (G1D), confirmed by 
clinical genotyping at a CLIA-certified laboratory. 
 
4.1.2. Stable on ketogenic diet at 2.5:1 to 4:1 ratio (i.e., no changes in ratio will 
have taken place for 2 months). The initiation of a ketogenic diet is previ- 
ous to -and thus is not part of- this study. 
 
4.1.3. Males and females 30 months to 35 years 11 months old, inclusive. 
 
4.2. 
Exclusion Criteria 
 
4.2.1. Subjects with evidence of independent, unrelated metabolic and/or genetic 
disease. 
 
4.2.2. Subjects with a chronic gastrointestinal disorder, such as irritable bowel 
syndrome, Crohn’s disease, or colitis that could increase the subject’s risk 
of developing diarrhea or stomach pain. 
 
4.2.3. Subjects with a BMI (body mass index) greater than or equal to 30. 
 
4.2.4. Subjects currently not on ketogenic diet. 
 
4.2.5. Women who are pregnant or breast-feeding may not participate. Women 
who plan to become pregnant during the course of the study, or who are 
unwilling to use birth control to prevent pregnancy (including abstinence) 

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may not participate. Females age 10 and over will be asked to provide a 
serum or urine sample for a pregnancy test via dipstick. Subjects will be 
asked to 
agree to abstinence or another form of birth control for the duration of the 
study. 
 
4.2.6. Allergy/sensitivity to C7. 
 
4.2.7. Previous use of triheptanoin less than 1 month prior to study initiation. 
 
4.2.8. Treatment with medium chain triglycerides in the last 24 hours. 
 
4.2.9. Subjects exhibiting signs of dementia, or diagnosed with any degenerative 
brain disorder (such as Alzheimer’s disease) that would confound as- 
sessment of cognitive changes, in the opinion of the investigator. 
 
4.2.10. Active drug or alcohol use or dependence that, in the opinion of the in- 
vestigator, would interfere with adherence to study requirements. 
 
4.2.11. Inability or unwillingness of subject or legal guardian/representative to 
give written informed consent, or assent for children age 10-17. 
 
4.2.12. Addition of a new antiseizure drug in the previous 3 months. 
 
4.3. 
Study Enrollment Procedures 
 
4.3.1. Recruitment 
 
Dr. Pascual is the Director of the Rare Brain Disorders Clinic at UT Southwestern 
Medical Center and Children’s Medical Center Dallas. This clinic currently pro- 
vides care for approximately 100 confirmed G1D subjects from around the United 
States. Dr. Pascual’s current subjects will be contacted by Dr. Pascual to deter- 
mine interest in participating in this research. Our experience has been that, due to 
the childhood manifestations of this disease, the chronic nature of symptoms, and 
the difficulty in finding effective treatments, these families and subjects are 
particularly eager for clinical trial opportunities. Our pilot study of G1D (8), which 
was conducted to establish the feasibility of the EEG protocol as well as providing 
other preliminary data, recruited 14 subjects in 15 days and had to decline as many 
as twice that number of interested subjects who made contact just after re- 
cruitment was complete. 
 
In addition, Dr. Pascual maintains a collaborative relationship with the Glut1 Defi- 
ciency Foundation, a community-based patient advocacy 501(c)(3) organization 
dedicated to supporting research in G1D. Dr. Pascual is an invited speaker to their 
annual meeting, and the G1D Foundation has expressed its willingness to support 
and promote our research efforts through their community boards and newsletters. 
 
Information regarding the trial will also be posted on the ClinicalTrials.gov and UT 
Southwestern websites, the latter of which includes a searchable database for 
current trials ongoing at UT Southwestern. 

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An additional recruitment tool is the web-based, patient-generated G1D patient 
registry. The registry is an IRB-approved, HIPAA-compliant inclusive question- 
naire that captures all relevant aspects of G1D natural history and therapies. The 
registry, which has been accessible for 1 year now, is housed in the UT South- 
western servers that contain the medical center medical records and currently has 
over 100 unique enrollees. 
 
4.3.2  Screening Log and Enrollment 
 
We anticipate enrolling approximately 8 subjects in Year 1 and 7 subjects in Year 
2. Because this study is resource intensive due to the inpatient stay, and be- 
cause it will be enrolling concurrently with Protocol 1 (year 1) and Protocol 2 
(year 2), enrollment at this rate will allow us to schedule around available re- 
sources of both personnel and facilities. This enrollment rate also allows for flexi- 
bility in scheduling the EMU with research patients, particularly in year 2. 
 
A screening log will be maintained in an excel spreadsheet, documenting how 
subjects learned about the trial (Dr. Pascual, community group, clinicaltrials.gov, 
etc.), who referred them to the trial, the reasons for ineligibility (if applicable), and 
the reasons for nonparticipation of eligible subjects. The research coordinator will 
meet with Dr. Pascual at the end of each clinic day to confirm eligible and ineligi- 
ble subjects seen during the day. The research coordinator will be responsible for 
screening the designated secure UT Southwestern email account, contacting in- 
terested subjects, and logging which subjects qualify and which subjects do not and 
why. 
 
Enrollment will open in month 1, although screening will begin prior to this month. 
We anticipate reaching 25% enrollment for this study in month 6, 50% enrollment in 
month 12, 75% enrollment in month 18, and 100% enrollment in month 24. 
 
Recruitment will be monitored monthly. If recruitment goals fail to be met within the 
first 6 months of opening enrollment, the recruitment log will be analyzed to clarify 
the reasons for lack of enrollment, and these reasons will be addressed if possible. 
In our experience, this population is eager for research studies and very willing to 
participate, even traveling from several states away to participate in research. 
 
If we have not met recruitment goals, we have several steps in place to improve 
recruitment. 
 
1. 
We will utilize our G1D Registry, which includes a clause to inform registered 
patients about clinical research, and reach out these patients if they have not been 
enrolled. This process will take approximately 1-2 weeks, and we will re- evaluate 
recruitment, based on scheduled visits, after 4 weeks. 
 
2. 
If recruitment is still lagging, or we have exhausted available patients in the 
registry, we will work with the Glut1 Deficiency Foundation. Per the FOA, re- 
searchers are encouraged to work with and engage patient groups. We have 
worked with the Glut1 Deficiency Foundation in various capacities over the past 

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several years and maintain an excellent working relationship with them , including 
making their broad patient base regularly aware of our research. The Glut1 
Deficiency Foundation will send an email to members with information regarding 
the trial, and encourage interested families to contact us if desired. This process 
will take 1-2 weeks, and recruitment will be re-evaluated after 4 weeks, based on 
scheduled visits. 
 
3. 
Finally, if we still experience a lack of patients, we will reach out to the G1D 
Research Consortium (G1DRC; which is not contributing support letters because 
the Consortium is not part of this proposal), which we have established for the 
broad purpose of clinical investigation and patient information. There are current- 
ly 10 U.S. institutions in the consortium, which cover virtually all densely populat- 
ed areas of the U.S. The relationship with Consortium members is excellent, as, 
even before the Consortium was formed, members had previously referred to us 
a total of 36 G1D patients for specialized neurological consultation. 
 
In addition, if enrollment is slower than anticipated, it is within the scope of this 
research to allow an additional 2 years to enroll (months 25-48). See Protocol 
Timeline below. 
 
Protocol Timeline 
 
 
4.3.3. Consent and Assent Procedures 
 
Subjects will be asked to verify basic eligibility for the trial prior to enrollment (age, 
diagnosis, if they currently are on dietary therapy) and to provide a copy of their 
current medical record at the time of enrollment, if they choose to participate. 
Interested subjects will be securely emailed a copy of the consent prior to their 
enrollment appointment. The Rare Brain Disorders Clinic maintains a dedicated 
email address (Rare.Diseases@UTSouthwestern.edu) for correspondence with 
current and prospective subjects and research participants. Interested patients 
may ask any questions via this email, or arrange a phone conversation to answer 
questions prior to traveling to Dallas for enrollment. Dr. Pascual or M.D. co-
investigator will consent the subjects in a private exam room. Each aspect of 

 
 
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the trial will be thoroughly explained to the legal guardian and subject. Time will be 
allowed for questions to be asked. The physician will explain that participation is 
voluntary, the decision not to participate does not affect the quality of their standard 
of care treatment with the physicians, and subjects may withdraw from the study at 
any time. Subjects ages 10 to 17 will be asked to provide their assent, and a legal 
guardian will be asked to sign the consent form. Subjects under the age of 10 are not 
required to sign assent. The subject’s legal guardian will be asked to sign the 
consent form for these subjects. 
 
Subjects and legal guardians will also have the HIPAA Authorization for Re- 
search explained to them, and again any questions will be answered. The sub- 
ject’s legal guardian will be asked to sign the HIPAA form. 
 
Subjects and their legal guardians will receive a signed copy of both the consent form 
and the HIPAA Authorization form. One copy will be placed in the research folder, and 
one copy will be placed in the subject’s medical record. 
 
Potential subjects who live out of state or outside the United States will have the 
option to consent to the study via telephone. Subjects will be provided a copy of the 
informed consent document, then a telephone call will be scheduled with Dr. Pascual. 
The process of obtaining informed consent will be conducted as outlined above. The 
subject will sign the consent form, then send the original copy of the informed consent 
to Dr. Pascual. A copy of the signed form from both parties will be emailed or mailed 
back to the family for their records.  
 
4.3.4. Group Assignment 
 
This is an open-label study; there is no group assignment. 
 
5. 
STUDY INTERVENTIONS 
5.1. Interventions, Administration, and Duration 
 
5.1.1. Triheptanoin: A triglyceride oil containing three odd-carbon chain-length fatty 
acids (i.e., a triglyceride of 7-carbon heptanoic acid). Triheptanoin will be taken 
4 times (approximately every 6 hours) by mouth for one day. It is dosed 4 
times per day, added to ketogenic diet meals (replacing some of the fat in 
each meal). Subjects will receive supplementation at 45% of daily caloric 
intake. The oil should be taken with meals, and will be mixed 
with the rest of the ketogenic diet nutrients for administration. 
 
5.1.2. Fifteen subjects will be enrolled in a 4 day proof of principle trial of trihep- 
tanoin. Administration of triheptanoin will be done in the Children’s Medical 
Center Dallas Epilepsy Monitoring Unit. 
 
5.1.3. Subjects will not be required to stop other medications. Subjects will be di- 
rected to maintain their usual medications, including rescue seizure medi- 
cations, as necessary for the course of the study. Subjects may have any 
clinical medical records transferred back to their referring physician at 
completion of the study. 
 

 
 
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5.1.4. Side Effects: 14 years of experience with C7 diet therapy in children and 
adults (including 14 G1D subjects, and a larger group of patients with fatty 
acid oxidation defects) has failed to reveal any significant adverse effects (9-
12). However, subjects may experience mild gastrointestinal upset or stomach 
pain, and mild diarrhea. Both of these side effects are usually resolved by 
lowering the initial dose of oil by one-half and gradually titrating 
up to the required dose. In addition, subjects who do not follow the rec- 
ommendations to reduce other fat intake in their diet may experience weight 
gain. Once oil is discontinued, careful monitoring of fat and calorie intake 
usually effectively reverses the weight gain. The data indicate no adverse 
effects on normal metabolism. A side effects questionnaire will be used to 
track any self-reported side effects. Patient safety information will be updated, 
if necessary, after completion of this trial. 
 
5.2. Handling of Study Interventions 
 
5.1.1. 5.2.1. Triheptanoin will be purchased from 1) Stepan Lipid Nutrition headquartered 
in Maywood, New Jersey, where the company has also a production facility. The oil 
is supplied in 25 kg containers under a current Material Transfer Agreement, and/or 
2) CKM Corporation headquartered in Racine, Wisconsin with the production 
facilitiy in Racine, Wisconsin. 
 
5.2.2. Stepan Lipid Nutrition and/or CKM Corporation will distribute the oil to the 
Investigational Pharmacy Services (IPS) at Children’s Medical Center. The 
pharmacists at the IPS will dispense the oil 4 times for each subject, during 
their inpatient stay. 
 
5.3. Concomitant Interventions 
 
5.3.1. Required Interventions: There are no additional required interventions. 
 
5.3.2. Prohibited Interventions: Subjects are prohibited from starting or changing 
dietary therapy or other oil-based dietary modifications (including ketogenic diet 
ratio or medium chain triglyceride therapy) while on study protocol. Subjects who 
feel this change is necessary will be withdrawn from the study for their own 
protection. Because of potential C7- supplemental dietary medium chain 
triglyceride interference, subjects may not have had medium chain triglyceride 
dietary supplements in the 24 hours before study initiation and must agree not to 
consume additional supplemental medium chain triglyceride while on this trial. In 
practice, subjects will simply replace any supplemental medium chain 
triglyceride with any other fat that they are currently consuming. 
 
5.3.3. Precautionary interventions: Subjects will be monitored by continuous EEG for 
the duration of C7 administration, and for approximately 18 hours after their 
last dose. If subjects experience breakthrough clinical seizures, Epilepsy 
Monitoring Unit physicians and nurses are trained to identify and treat these 
seizures. Study physicians will be contacted as soon as possible for treatment 
directives or, if after the event, subject status update, but in the event of an 

 
 
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acute epileptic crisis, staff on hand are qualified and capable of handling the 
event. 
 
5.4. Adherence Assessment: All C7 is administered on an inpatient basis. There are no 
adherence assessments. 
 
 

 
 
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6.  CLINICAL AND LABORATORY EVALUATIONS 
6.1. Schedule of Evaluations 
Evaluation 
Screen 
Day 1 
Pre-Entry and Entry 
Day 2 
Day 3 
Day 4 
Informed Consent 
 
X 
 
 
 
Documentation of 
Disease/Disorder 
X 
X 
 
 
 
Medical/Treatment 
History 
X 
 
 
 
X1 
Clinical Assessment 
 
X 
X 
X 
X1 
Targeted Physical 
Exam 
 
X 
 
 
 
X1 
Side Effect 
Assessment 
 
X 
X 
X 
X2 
Pregnancy Testing 
 
X 
 
 
 
Nutritional  
Assessment 
 
X 
 
 
 
Seizure Count 
 
X 
 
X 
X 
Inpatient 
 
Admit: Noon 
 
D/C: 
Noon 
 
Continuous EEG 
 
X 
X 
½ 
day
½h
 
Laboratory Evaluations: 
Hematology, Chemistry 
 
X 
X 
X 
X 
Laboratory Evaluations: 
Random glucose, 
Beta-hydroxybutyrate 
 
 
X 
AM & PM 
X 
AM & at D/C 
 
Blood collection to 
measure C7 ketones1 
 
X 
X 
X 
X 
Triheptanoin 
Supplementation 
 
 
X 
 
 
1Optional: completed only at discretion of PI or sub-Is 
2VA Toxicity Scale optional & completed only at discretion of PI or Sub-Is 
6.2. Timing of Evaluations 
 
6.2.1. Pre-Entry Evaluations 
 
6.2.1.1. 
Screening 
In order to evaluate subjects’ eligibility to participate prior to traveling to Dallas, a waiver 
of HIPAA Authorization will be obtained only for the purposes of obtaining information 
regarding age, diagnosis, height, weight, current dietary therapy, and medical history. 
Once the subject’s basic eligibility has been confirmed, the subject will be scheduled for 
a screening visit in order to be consented and to continue the screening process. 
 
After signing the informed consent, subjects will finish the screening for study eligibility. 
All screening evaluations to determine eligibility must be completed within one day prior 
to study entry. Screening and Pre-Entry evaluations may occur concurrently. All 
screening activities are consistent with standard of care. Screening includes 
documentation of diagnosis and medical history. 
 

 
 
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6.2.1.2. 
Pre-Entry Day 1 
The first day of the subject’s visit is Pre-Entry Day 1. Pre-Entry assessments consist of 
clinical assessment, targeted physical exam, side effect assessment, pregnancy testing 
if appropriate, and a seizure count. 
 
6.2.2. On-Study/On-Intervention Evaluations 
 
6.2.2.1. 
Entry Day 1 
Subjects will be admitted for a 48 hour inpatient stay for oil administration and 
monitoring. Entry evaluations will be done within a day of pre-entry and consist of a 
nutritional assessment, and a blood draw to evaluate hematology and blood chemistry, 
including a random glucose. We will also obtain blood that is left over from the samples 
above (if available) or draw an additional 3 mL of blood, if needed, to measure C7 ketones. The 
collection of this blood for measurement of ketones is optional. A continuous EEG will be 
completed on subjects over the 48 hour inpatient stay. A peripheral IV will be placed to 
allow for immediate treatment of breakthrough seizures, should they occur. 
 
6.2.2.2. 
Day 2 
 
Subjects will be administered C7 starting on the morning of Day 2. Subjects will be given 
oil at a rate of 45% of their daily caloric intake, divided into 4 doses (breakfast, lunch, 
dinner, and before bed). A clinical assessment and a side effect assessment will be done. 
Subjects will be maintained on continuous EEG for the duration of C7 administration. 
Subjects will receive their final dose in the evening on Day 2. Subjects will have a blood 
draw to evaluate hematology and blood chemistry. Subjects will undergo a random 
glucose and beta-hydroxybutyrate level in the morning with their first dose of C7 and at 
bedtime with their last dose of oil. We will also obtain blood that is left over from the samples 
above (if available) or draw an additional 3 mL of blood, if needed, to measure C7 ketones. The 
collection of this blood for measurement of ketones is optional. 
 
6.2.2.3. 
Day 3 (Intervention Discontinuation Evaluations) 
 
Subjects will remain inpatient until approximately noon on Day 3 to ensure no untoward 
withdrawal effects from C7. A clinical assessment, a side effect assessment, and a 
seizure count will be done. Subjects will have a blood draw to evaluate hematology and 
blood chemistry. Subjects will undergo a random glucose and beta- hydroxybutyrate 
level in the morning and just prior to discharge. We will also obtain blood that is left over 
from the samples above (if available) or draw an additional 3 mL of blood, if needed, to 
measure C7 ketones. The collection of this blood for measurement of ketones is optional. EEG 
will be stopped just prior to discharge.  
 
6.2.3. 
Final On-Study Evaluations 
Subjects will return for a discontinuation visit on Day 4. Subjects will complete a seizure 
count, limited side effect assessment (Hague Side Effect Scale), and have non-fasting blood 
drawn to evaluate hematology and chemistry. We will also obtain blood that is left over from the 
samples above (if available) or draw an additional 3 mL of blood, if needed, to measure C7 ketones. 
The collection of this blood for measurement of ketones is optional. Medical history, clinical 
assessment, targeted physical exam, and VA Toxicity Scale are optional and will be completed 

 
 
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only at PI or sub-Investigator discretion. 
 
This visit will complete their participation, and subjects will be discontinued from the 
study. 
 
6.2.4. Pregnancy 
Subjects will be inpatient for the duration of C7 administration. Subjects receive a pregnancy 
test prior to study entry, and no pregnancy is anticipated during the 4 day participation. 
 
6.3. Special Instructions and Definitions of Evaluations 
 
6.3.1. Informed Consent 
Patients will be brought into a private exam room for the consent process. The coordinator 
will introduce the study, explain the procedures, the patient rights and responsibilities, and 
the risks and benefits of the study. Dr. Pascual or M.D. co-investigator will then discuss any 
additional questions regarding the study, ensure the patient and family understand the 
protocol, their responsibilities, and their commitment to the research. Once the Dr. Pascual or 
co-investigator is satisfied with the patient and family’s understanding and intent to participate 
in the research, the patient and family will sign the consent form. If the subject is age 10-17 
years, the subject must assent to the research study in order to participate. Dr. Pascual or co-
investigator will then sign the consent form documenting that consent was obtained. 
 
The institutional research HIPAA form will also be reviewed with the family and any 
questions answered. Once the research team feels the subject and family understand the 
HIPAA form, parent or subject signatures will be obtained. 
 
Once the consent and HIPAA forms have been signed by the subject, parents, and PI or 
M.D. co-investigator, study procedures may be initiated. The research coordinator will 
create copies of the consent and HIPAA forms: one copy of each form will be returned to the 
subject and family, and the original of each document will be filed in the subject’s research 
file for the duration of the subject’s participation. 
 
6.3.2. Documentation of Glucose Transporter Type I Deficiency (G1D)  
Subjects must provide results of genotyping obtained in a CLIA-certified laboratory 
identifying the GID mutation. 
 
6.3.3. Medical/Treatment History 
Procedure location: Children’s Medical Center Rare Brain Disorders Clinic. Facilitators: 
Principal Investigator or physician co-investigators. All subjects’ symptoms, past medical 
history, and current and past treatments will be obtained using a standardized questionnaire 
that we have used extensively in metabolic encephalopathies to ensure that symptoms 
anticipated in G1D are sufficiently characterized (13, 14). For example, seizure frequency 
(the main indicator of neural dysfunction) is captured by this tool. However, in order to avoid 
ascertainment bias, a wide range of general questions related to all systems is included. 
This assessment takes approximately 30 minutes. 
 
6.3.4. Clinical Assessments/Targeted Physical Exam 
Procedure location: Children’s Medical Center Rare Brain Disorders Clinic and Epilepsy 
Monitoring Unit. Facilitators: Dr. Pascual or physician co-investigators. We will utilize a 

 
 
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standardized scoring system previously used by us to assess the clinical findings on ex- 
amination (13, 14). The tool focuses on the following domains: (a) height, weight, and head 
circumference; (b) general medical exam; (c) general neurological exam; (d) cranial nerves; 
(e) stance and gait; (f) involuntary movements; (g) sensation; (h) cerebellar function; (i) 
muscle bulk, tone and strength; (j) myotatic reflexes, (k) presence of Babinski signs; and (l) 
other findings. Results of these domains are scored as normal or abnormal and summarized 
as a total score with 76 being normal. This assessment takes approximately 30 minutes. 
 
6.3.5. Side Effect Assessment 
Side effects will be assessed using the Hague Side Effect Scale (15) and the VA Toxicity 
Scale (16), which are part of the Common Data Elements for NINDS. These scales, 
between them, measure side effects of anti-epileptic medications, including some 
gastrointestinal symptoms and systemic effects measured by our safety blood work. Side 
effects reported by the family but not found on the scales will be noted. These scales take 
approximately 20 minutes to complete. 
 
6.3.6. Pregnancy testing 
Serum or urine pregnancy testing will be done to test for pregnancy. As the majority of our 
subjects are minors, we do not anticipate the timing will interfere with C7 initiation; however, 
C7 will not be initiated until the pregnancy results are returned and are confirmed negative. 
 
6.3.7. Nutritional Assessment 
The registered dietician will do a complete review of the subject’s caloric intake, and work with 
PI to determine the optimal amount of oil based on the current caloric intake and ketogenic 
diet ratio. The consult will take approximately 45 minutes. 
 
6.3.8. Seizure count 
Subjects and caregivers will be asked to count any seizures they note during the inpatient 
stay, from prior to oil administration to discharge on Day 3. They will be given a log to record 
time and description of any visible seizures. 
 
6.3.9. Electroencephalogram 
The subjects will undergo continuous EEG recording of brain wave activity for 
approximately 48 hours during each inpatient stay. The EEG will involve placement of an 
electrode cap. The subject will be fitted with a cap containing up to 32 electrodes which 
rest against their scalp, and which allow their brain electrical activity (EEG) to be recorded.  
An additional electrode will also be placed directly to the skin in the chest. All skin 
preparation equipment coming into contact with skin is discarded after a single use, and 
electrodes and caps are cleaned and disinfected immediately after use in accordance with 
published guidelines. The EEG recording is harmless and painless. Only the application of 
the electrode cap may involve mild, temporary discomfort. At the end of the session we will 
remove the cap and electrodes, and help clean the skin if necessary. 
 
6.3.10. Laboratory Evaluations 
Hematological and chemical profiles (Comprehensive metabolic panel, lipid panel, , Lactate 
Whole Blood, Triglycerides, HDL Cholesterol, LDL Cholesterol, Cholesterol , Complete 
Blood Count, random plasma glucose, and beta-hydroxybutyric acid (a ketone body 
generated by ketogenic diets) will be measured by standard clinical laboratory methods and 
compared to normal values established in each laboratory. In addition, subjects will have 

 
 
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blood drawn via IV for random plasma glucose and beta-hydroxybutyric acid levels in the 
morning and evening on Day 2 and in the morning and before discharge on Day 3. 
Measurement of C7 ketones will be conducted by a collaborating research laboratory. 
 
6.3.11. Triheptanoin Administration 
Triheptanoin administration will be accomplished in the Epilepsy Monitoring Unit located in 
the Children’s Medical Center. Initiation will be completed under the supervision of Dr. 
Pascual or one of the physician investigators. 
 
6.3.12. Adherence Assessments 
All C7 administration will be done on an inpatient basis, over one day. No adherence as- 
sessments are completed. 
 
7. 
MANAGEMENT OF ADVERSE EXPERIENCES 
Previous experience with C7 oil in different populations has yielded no serious adverse 
effects. Due to the limited nature of the use of C7 oil, there is no data available on how 
frequent the following side effects occur, nor if there are differences between normal diet 
or ketogenic diet. 
 
Breakthrough Seizures: There is the possibility that the administration of C7 oil may 
result in the subject dropping out of ketosis very quickly, which may lead to 
breakthrough seizures.  Management of these breakthrough seizures will follow 
standard of care protocol, which could include IV or rectally administered anti-
convulsant medications. 
 
Diarrhea: Subjects who experience diarrhea may be instructed to increase the amount of 
fiber consumed with each meal. In addition, C7 will be administered in a fat free, sugar 
free food item, such as yogurt or pudding, and subjects are instructed to consume this 
food over 30 minutes in order to minimize diarrhea. Subjects who cannot tolerate the 
maximum tolerable dose will be discontinued from the study. 
 
Stomach pain: Subjects who experience stomach pain at any time during the treatment 
will, under the direct supervision of Dr. Pascual or M.D. co-investigator, be assessed for 
severity.  If subjects cannot tolerate the recommended dose due to severe stomach 
pain, they will be discontinued from the study. 
 
Weight gain: Although weight gain is a possible side effect of C7 ingestion, it is a long- 
term effect, and we do not anticipate significant weight gain over the course of one day. 
 
8. 
CRITERIA FOR INTERVENTION DISCONTINUATION 
Triheptanoin supplementation will be discontinued if any of the following occur: 
 
• Any of the cited or other adverse experiences become intolerable to the subject 
• Metabolic syndrome develops as assessed by glucose and lipid profiles 
• Any elevation above laboratory normal range in hepatic transaminases or 
creatinine is noted 
• Any blood cell count abnormality outside laboratory normal range develops 
• Non-compliance occurs 

 
 
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• 
Severe intercurrent illnesses take place 
• Severe seizures that are unusual for the subject take place 
 
Subjects who discontinue due to the above reasons will be asked to return for a final re- 
search visit to complete exit procedures and receive referrals for ongoing care if neces- 
sary. Subjects who are discontinued due to adverse events will be followed via daily, al- 
ternate-day or weekly phone calls to assess resolution of the adverse event. 
 
9. 
STATISTICAL CONSIDERATIONS 
9.1. General Design Issues 
 
The main aim of this proof of principle trial is to evaluate the compatibility of C7 with ke- 
togenic diet in subjects diagnosed with G1D. This protocol will yield data that allow a 
go/no-go decision regarding whether C7 should proceed to an efficacy trial: 
 
If EEG, clinical seizure activity, glycemia and ketosis (blood beta-hydroxybutyrate level) 
under the ketogenic diet remain unaltered (i.e., unchanged from normal laboratory value 
ranges) in at least 3 out of 5 G1D subjects in each age group after the partial substitu- 
tion of ketogenic diet fat with C7, we will confirm compatibility of C7 with ketogenic diet 
and recommend proceeding to an efficacy trial for C7. 
 
The sample size estimation for this optimal two-stage design is given in Section 9.3. 
 
9.2. Outcomes 
 
9.2.1. Primary outcome 
 
9.2.1.1. 
EEG 
C7 metabolism will not interfere with previously-acquired ketosis in G1D, 
as measured by no change in EEG from pre-C7 baseline. 
 
Subjects receiving C7 supplementation will experience no interference 
with ketosis, as measured by no change in EEG. 
 
9.2.1.2. Laboratory Assessments 
C7 metabolism will not interfere with previously-acquired ketosis in G1D, 
as measured by no increase in observable seizure rate and no clinically 
relevant changes glycemia and ketosis, as measured by random glucose 
levels and beta-hydroxybutyrate levels, which will remain within the pre- 
enrollment clinically acceptable ranges (i.e., the new values will typically 
be within 2SD of previous values, using as SD the SD of the normal val- 
ues as determined by the laboratory). 
 
Subjects will experience no clinically relevant changes in observable sei- 
zures, random plasma glucose, or beta-hydroxybutyrate levels, as com- 
pared to the baseline values defined above. 

 
 
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9.3. Sample Size and Accrual 
 
In this exploratory pilot study, we will recruit 5 subjects in each of three age groups for a 
total of 15 subjects. The sample size is not justified because this is an exploratory pilot 
study that will yield data aimed to enable important future combined or comparative 
studies. We expect to complete the enrollment of study within 24 months. 
 
9.4. Data and Safety Monitoring 
 
A Monitoring Committee (MC) consisting of 5 external pediatric neurologists and a pa- 
tient advocate has been assembled. The committee will be chaired by Dr. Marc Patter- 
son of the Mayo Clinic in Rochester, MN. Dr. Patterson and the committee will review 
the side effect and adverse event data at each enrollment milestone (25%, 50%, 75%, 
and 100%), and additionally as recommended by the committee. The committee will 
meet via Skype or web conference at these milestones, and Dr. Patterson will com- 
municate the results to PI, along with any recommendations the committee had regard- 
ing safety. The current committee is composed of the members listed in the following 
table. 
 
Monitoring committee at a glance 
Member 
Affiliation 
Credentials 
Patterson, chair 
Director of Pediatric and Ado- 
lescent Neurology, Mayo Clinic 
Neurometabolic disorders, clini- 
cal trials (Niemann-Pick type C 
disease, lysosomal storage dis- 
eases) 
DiMauro 
Director emeritus, H. Houston 
Merritt Clinical Research Center 
Columbia University 
Neurometabolic disorders, clini- 
cal trials (mitochondrial and neu- 
romuscular diseases). Member, 
Institute of Medicine 
Kossoff 
Medical director, Ketogenic Diet 
Program, Johns Hopkins Uni- 
versity 
Ketogenic diet and alternative 
therapies. Coauthor of Treat- 
ment of Pediatric Neurologic 
Disorders and the 5th edition of 
The Ketogenic Diet 
Rapaport 
Patient advocacy representa- 
tive: Glut1 Deficiency Founda- 
tion member (Education Com- 
mittee) 
Ph.D. (Environmental Engineer- 
ing and Chemistry). Past Asso- 
ciate Director, Product Safety 
and Regulatory Affairs, Procter & 
Gamble. Led Department con- 
sisting of > 100 toxicologists in 
U.S., Europe and Asia. 
Ronen 
Professor of Pediatrics, McMas- 
ter University 
Identified index case of G1D in 
1989 (De Vivo el al., NEJM 
325:703-9, 1991). Master’s de- 
gree in clinical research 
methodology. Director of 
internationally-acclaimed 
research program in quality of 
life in children with epilepsy  

 
 
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Roach 
Section Chief of Pediatric 
Neurosciences at Dell 
Children’s Medical Center of 
Central Texas; Professor, 
Department of Neurology, 
University of Texas at Austin 
Authored or edited 9 medical text 
books and more than 200 journal 
articles, many focusing on 
genetic neurological disorders or 
stroke in children and adults.  
Editor-in-chief of Pediatric 
Neurology and former president 
of the Child Neurology Society 
 
If a physician committee member determines that they are no longer able to serve on 
the MC, the other committee members will be asked for recommendations for a re- 
placement member, in consultation with PI. A replacement member will be identified, 
and the approval of NINDS will be sought prior to confirming the replacement. 
 
In the event that the patient advocate representative makes the decision to step down, 
the board of the Glut1 Deficiency Foundation will be consulted, and a request for a re- 
placement member will be made. The approval of NINDS will be sough prior to con- 
firming the replacement of this committee member. 
 
9.5. Data Analyses 
 
Descriptive statistics will be computed for each group and combined age group in this 
pilot exploratory study. For normally distributed, continuous data, means and standard 
deviations will be used to describe the demographic and clinical characteristics of the 
patient population participating in the study. Medians, quartiles, and ranges will be used 
to describe characteristics of the patient population when the data are continuous, non- 
normally distributed. For categorical or dichotomous variables, the frequency or the 
proportion will be reported. The proportion of patients who do not alter EEG in subjects 
currently receiving the ketogenic diet will be computed along with the corresponding 
95% confidence interval using the exact binomial method. The proportion of patients 
who have stable blood glucose and beta hydroxybutyrate levels during acute and long- 
term C7 supplementation will be computed using exact binomial method. 
 
Paired t-tests or nonparametric one-sample signed tests will be conducted to test if 
there were significant changes in EEG and neurological performance indices such as 
ataxia in G1D patients receiving a normal diet between pre-C7 and post-C7. The 
objective of this study is to enable future combined or comparative studies to evaluate 
C7 comparability with the ketogenic diet by evaluating EEG and preservation of 
glycemia and ketosis. Descriptive statistics will be computed to inform (but not to 
determine; per the FOA) the sample size needed for a future larger study. 
 
10. DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE REPORTING 
10.1. 
Records to Be Kept 
 
All signed informed consent forms will be maintained in a locked filing cabinet 
accessible only to the Dr. Pascual, Clinical Director, and research coordinator. 

 
 
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This cabinet is located in a limited-access room which requires an authorized 
badge to enter. 
 
All records collected for research-only purposes (research EEG, metabolic as- 
says) will be maintained in a secure fashion. Paper records will be maintained in 
a locked filing cabinet in a limited-access room. Electronic records will be main- 
tained on an internal, secure UTSW server accessible only by authorized 
username and password. These servers are backed up nightly, are HIPAA and 
HiTECH compliant, and are behind the same level of security as UT Southwest- 
ern and Children’s Medical Center Dallas’ medical records. 
 
Subject’s will be assigned a study ID, and all materials collected for research 
purposes will be de-identified using this study ID, including data and case report 
forms. A file containing the link will be maintained for the duration of active study 
procedures and during data cleaning. Once the data has been cleaned, the file 
containing the link to patient ID will be deleted and destroyed. 
 
Records collected for clinical and research purposes (e.g., blood tests and EEGs 
completed at Children’s Medical Center) will become part of the subject’s medical 
record at Children’s Medical Center and may be copied and transferred to the 
subject’s primary referring physician at the patient request. 
 
The investigator-sponsor will maintain records in accordance with Good Clinical 
Practice guidelines; to include: 
 
• FDA correspondence related to the IND application and Investigational Plan; in- 
cluding copies of submitted Form FDA 3500 A, supplemental IND applications, 
current investigator lists, progress reports, and failure to obtain informed consent 
reports; 
• IRB correspondence (including approval notifications) related to the clinical pro- 
tocol; including copies of adverse event reports and annual or interim reports; 
• Current and past versions of the IRB-approved clinical protocol and correspond- 
ing IRB-approved consent form(s) and, if applicable, subject recruitment adver- 
tisements. 
• Signed Investigator’s Agreements and Certifications of Financial Interests of Clin- 
ical Investigators; 
• Curriculum vitae (investigator-sponsor and clinical protocol sub-investigators); 
• Certificates of required training (e.g., human subject protections, Good Clinical 
Practice, etc.) for investigator-sponsor and listed sub-investigators; 
• Normal value(s)/range(s) for medical/laboratory/technical procedures or tests in- 
cluded in the clinical protocol; 
• Laboratory certification information; 
• Instructions for on-site preparation and handling of the investigational study 
treatment (i.e., if not addressed in the clinical protocol); 
• Signed informed consent forms; 

 
 
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• Completed Case Report Forms; signed and dated by investigator-sponsor; 
• Source Documents or certified copies of Source Documents; 
• Monitoring visit reports; 
• Copies of investigator-sponsor correspondence to sub-investigators, 
including notifications of adverse effect information; 
• Subject screening and enrollment logs; 
• Subject identification code list; 
• Investigational drug accountability records, including documentation of 
disposal; 
• Final clinical study report. 
 
The investigator-sponsor will retain the specified records and reports for up to 
2 years after the marketing application is approved for the investigational 
product; or, if a marketing application is not submitted or approved for the 
investigational drug, until 2 years after investigations under the IND have 
been discontinued and the FDA so notified. 
 
10.2. 
Role of Data Management 
 
This is a single site study; there are no other clinical sites or statistical 
center. The CTSA division at UT Southwestern Medical Center will create 
and maintain our database for this study. 
 
10.3. 
Quality Assurance 
 
Study personnel and physicians will be trained prior to protocol initiation. Dr. 
Pascual will participate in several subject intake and evaluations with the 
physician investigators throughout the study period to ensure quality of 
clinical exams. In addition, Dr. Pascual will review records collected during 
these clinical exams to ensure completeness and accuracy. 
 
The Clinical Director will supervise training of all support personnel, including 
the research coordinator. She will provide monitoring of regulatory 
compliance on all aspects of the study, including review of research records 
and consent forms. The research coordinator will be responsible for 
submitting all IRB documentation, but will work with the Clinical Director 
when necessary to ensure compliance. 
 
Dr. Pascual and Clinical Director will work together to ensure all personnel 
are properly trained on their role in the project, and will work together on all 
federal submissions to remain compliant with reporting requirements. 
 
In the event that monitoring authorities request records, Dr. Pascual and the 
Clinical Director will work together with the authorities to provide all requested 
and required documentation. 
 
 
 

 
 
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10.4. 
Adverse Experience Reporting 
Adverse experiences will be collected from subjects at each daily visit. Adverse 
experiences will be recorded using Adverse Event forms from the NINDS com- 
mon data elements for epilepsy website (VA toxicity scale). Adverse events will 
be reported following all requirements set forth by the FDA, OHRP, and local 
IRB. 
 
10.4.1.Adverse event definitions 
 
Adverse effect. Any untoward medical occurrence in a clinical study of an inves- 
tigational product, regardless of the causal relationship of the problem with the 
product. 
 
Associated with the investigational product. There is a reasonable possibility that 
the adverse effect may have been caused by the investigational product. 
 
Disability. A substantial disruption of a person’s ability to conduct normal life 
functions. 
 
Life-threatening adverse effect. Any adverse effect that places the subject, in the 
view of the investigator-sponsor, at immediate risk of death from the effect as it 
occurred (i.e., does not include an adverse effect that, had it actually occurred in 
a more severe form, might have caused death). 
 
Serious adverse effect. Any adverse effect that results in any of the following 
outcomes: death, a life-threatening adverse effect, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disabil- 
ity/incapacity, or a congenital anomaly/birth defect. 
 
Hospitalization shall include any initial admission (even if less than 24 hours) to a 
healthcare facility as a result of a precipitating clinical adverse effect; to include 
transfer within the hospital to an intensive care unit. Hospitalization or prolonga- 
tion of hospitalization in the absence of a precipitating, clinical adverse effect 
(e.g., for a preexisting condition not associated with a new adverse effect or with a 
worsening of the preexisting condition; admission for a protocol-specified pro- 
cedure) is not, in itself, a serious adverse effect. 
 
Unexpected adverse effect. Any adverse effect, the frequency, specificity or se- 
verity of which is not consistent with the risk information described in the clinical 
study protocol(s) or elsewhere in the current IND application, as amended. 
 
Unanticipated adverse effect. Any serious adverse effect on health or safety or 
any life-threatening problem or death caused by, or associated with, an investiga- 
tional product, if that effect, problem, or death was not previously identified in na- 
ture, severity, or degree of incidence in the investigational plan or IND application 
(including a supplementary plan or application), or any other unanticipated seri- 

 
 
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ous problem associated with an investigational product that relates to the rights, 
safety, or welfare of subjects. 
 
10.4.2. Recording and assessment of adverse effects. 
 
All observed or volunteered adverse effects (serious or non-serious) and abnor- 
mal test findings, regardless of treatment group, if applicable, or suspected caus- 
al relationship to the investigational product will be recorded in the subjects’ case 
histories. For all adverse effects, sufficient information will be pursued and/or ob- 
tained so as to permit 1) an adequate determination of the outcome of the effect 
(i.e., whether the effect should be classified as a serious adverse effect) and; 2) 
an assessment of the casual relationship between the adverse effect and the in- 
vestigational product. 
 
Adverse effects or abnormal test findings felt to be associated with the investiga- 
tional product will be followed until the effect (or its sequelae) or the abnormal 
test finding resolves or stabilizes at a level acceptable to the investigator- 
sponsor. 
 
10.4.3 Abnormal test findings: 
 
An abnormal test finding will be classified as an adverse effect if one or more of 
the following criteria are met: 
 
• The test finding is accompanied by clinical symptoms. 
 
• The test finding necessitates additional diagnostic evaluation(s) or medi- 
cal/surgical intervention; including significant additional concomitant drug or other 
therapy. (Note: simply repeating a test finding, in the absence of any of the other 
listed criteria, does not constitute an adverse effect.) 
 
• The test finding leads to a change in study dosing or exposure or discontinuation 
of subject participation in the clinical study. 
 
• The test finding is considered an adverse effect by the investigator-sponsor. 
 
10.4.4.Causality and severity assessment: 
 
The investigator-sponsor will promptly review documented adverse effects and 
abnormal test findings to determine 1) if the abnormal test finding should be clas- 
sified as an adverse effect; 2) if there is a reasonable possibility that the adverse 
effect was caused by the investigational product; and 3) if the adverse effect 
meets the criteria for a serious adverse effect. 
 
If the investigator-sponsor’s final determination of causality is “unknown and of 
questionable relationship to the investigational product”, the adverse effect will be 

 
 
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classified as associated with the use of the investigational product for reporting 
purposes. If the investigator-sponsor’s final determination of causality is “un- 
known but not related to the investigational product”, this determination and the 
rationale for the determination will be documented in the respective subject’s 
case history. 
 
10.4.5.Reporting of adverse effects to the FDA 
 
The investigator-sponsor will submit a completed Form FDA 3500 A to the FDA 
for any observed or volunteered adverse effect that is determined to be an 
unanticipated adverse effect. A copy of this completed form will be provided to all 
participating sub-investigators. 
 
The completed Form FDA 3500 A will be submitted to the FDA as soon as possi- 
ble and, in no event, later than 10 working days after the investigator-sponsor 
first receives notice of the adverse effect. 
 
If the results of the sponsor-investigator’s follow-up evaluation show that an ad- 
verse effect that was initially determined to not constitute an unanticipated ad- 
verse effect does, in fact, meet the requirements for reporting; the investigator- 
sponsor will submit a completed Form FDA 3500 A as soon as possible, but in no 
event later than 10 working days, after the determination was made. 
 
For each submitted Form FDA 3500 A, the sponsor-investigator will identify all 
previously submitted reports that that addressed a similar adverse effect experi- 
ence and will provide an analysis of the significance of newly reported adverse 
effect in light of the previous, similar report(s). 
 
Subsequent to the initial submission of a completed Form FDA 3500 A, the in- 
vestigator-sponsor will submit additional information concerning the reported ad- 
verse effect as requested by the FDA. 
 
10.4.6.Reporting of adverse effects to the responsible IRB. 
 
In accordance with applicable policies of the University of Texas Southwestern 
Medical Center Institutional Review Board (IRB), the investigator-sponsor will re- 
port, to the IRB, any observed or volunteered adverse effect that is determined to 
meet all of the following criteria: 1) associated with the investigational product; 2) 
a serious adverse effect; and 3) an unexpected adverse effect. Adverse event 
reports will be submitted to the IRB in accordance with the respective IRB proce- 
dures. 
 
Applicable adverse effects will be reported to the IRB as soon as possible and, in 
no event, later than 10 calendar days following the investigator-sponsor’s receipt 
of the respective information. Adverse effects which are 1) associated with the 
investigational drug or, if applicable, other study treatment or diagnostic prod- 

 
 
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uct(s); 2) fatal or life-threatening; and 3) unexpected will be reported to the IRB 
within 24 hours of the investigator-sponsor’s receipt of the respective information. 
 
Follow-up information to reported adverse effects will be submitted to the IRB as 
soon as the relevant information is available. If the results of the sponsor- 
investigator’s follow-up investigation show that an adverse effect that was initially 
determined to not require reporting to the IRB does, in fact, meet the require- 
ments for reporting; the investigator-sponsor will report the adverse effect to the 
IRB as soon as possible, but in no event later than 10 calendar days, after the 
determination was made. 
 
 
 
11. HUMAN SUBJECTS 
 
11.1. 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document and any subsequent 
modifications will be reviewed and approved by the IRB committee responsible 
for oversight of the study. A signed consent form will be obtained from the 
subject. For subjects who cannot consent for themselves, such as those below 
the legal age, a parent, legal guardian, or person with power of attorney, must 
sign the consent form; additionally, the subject's assent must also be obtained if 
he or she is able to understand the nature, significance, and risks associated 
with the study. The consent form will describe the purpose of the study, the 
procedures to be followed, and the risks and benefits of participation. A copy 
of the consent form will be given to the subject, parent, or legal guardian, and this 
fact will be documented in the subject’s record. 
 
11.2. 
Subject Confidentiality 
 
All laboratory specimens, evaluation forms, reports, video recordings, and other 
records that leave the site will be identified only by the Study Identification Num- 
ber (SID) to maintain subject confidentiality. All records will be kept in a locked file 
cabinet. All computer entry and networking programs will be done using SIDs 
only. Clinical information will not be released without written permission of the 
subject, except as necessary for monitoring by IRB, the FDA, the NINDS, the 
OHRP, the sponsor, or the sponsor’s designee. 
 
11.3. 
Study Modification/Discontinuation 
 
The study may be modified or discontinued at any time by the IRB, the NINDS, 
the OHRP, the FDA, or other government agencies as part of their duties to en- 
sure that research subjects are protected. 

 
 
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12. ETHICAL CONSIDERATIONS 
 
12.1. 
Risk/benefit 
assessment 
Prior experience with triheptanoin has seen no adverse events in 
approximately 
100 patients (adults and pediatric). Side effects risks (weight gain and 
gastrointestinal distress, diarrhea, and nausea) do not persist after 
discontinuation or appropriate modification of diet. Extensive laboratory 
tests will be completed in order to monitor for any changes in patient health 
status, as well as continuous EEG in a specialized epilepsy unit. 
 
There are no direct benefits anticipated for participants. However, benefits 
to other patients on ketogenic diet in the future potentially include 
improvement in movement symptoms (e.g., ataxia) and improvement in 
neuropsychological functioning. For these reasons, we find the risk/benefit 
assessment to be positive. 
 
12.2 Pediatric 
Populations 
Although this medical food is not yet approved for use in adults, the need for 
early intervention in many neurological disorders has led us to propose this 
trial. As mentioned previously, there is no history, in our experience, of 
adverse events related to triheptanoin use in either adult populations or in 
our small pilot sample. Additionally, subjects with G1D typically manifest 
symptoms very young, and it is still unclear as to whether impairment in 
adulthood is the result of the disorder or of chronic, unmanageable seizures 
throughout childhood and adolescence. Finally, this rare disorder has no 
treatment options that address all facets of the disorder: seizures, 
movement disorders, and neuropsychological impairment ([4] and personal 
observations). Very few children with G1D grow into adults who are capable 
of holding a job and living independently (personal observations of PI), 
which describes a critical need for improvement in treatment for this 
population. 
 
13. PUBLICATION OF RESEARCH FINDINGS 
 
 
Any presentation, abstract, or manuscript will be made available for review by the 
NINDS prior to submission. All publications will meet ethical requirements for 
reporting patient data and institutional requirements for reporting conflict of 
interest. 
 
 
 

 
 
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