Conditions: ALS
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: yes

Brief summary:
The causes of ALS are largely unknown. However, mitochondrial dysfunction, resulting in impaired energy production, oxidative stress and apoptosis, may play a key role in ALS progression. Triheptanoin can improve mitochondrial function and energy production and therefore has potential for slowing ALS progression. Indeed, triheptanoin slowed motor neuron loss and delayed the onset of weakness in a mutant SOD1 model of ALS. This pilot trial will determine if Triheptanoin is safe tolerable, alters biomarkers of brain energy metabolism and oxidative stress, and slows functional decline in people with ALS.

Detailed description:
This is an open label, prospective cohort study of 10 people with ALS (PALS) from the Duke ALS Clinic. The first 5 enrolled PALS (Group 1) will receive standard ALS care for the first month, then standard care plus Triheptanoin for the next 5 months. The next 5 enrolled PALS (Group 2) will receive standard ALS care plus Triheptanoin for 6 months (Figure 1). All Group 1 and Group 2 PALS who complete this 6-month study will have an option for Triheptanoin treatment extension for an additional 12 months. In addition to the PALS, there will also be 5 healthy controls enrolled (Group 3), people that do not have ALS or any other neurodegenerative disease). These participants will not receive any treatment; the only outcome measure they will complete is serum and urine biomarker testing at screening/baseline, month 1 and month 6.

The rationale for delaying triheptanoin treatment in one group is to look for differences in MR spectroscopy related to treatment at the 1 month time point. The target triheptanoin dose for this study is 1g/kg/d. This target dose was selected because it was safe and tolerable and altered brain MR spectroscopy in patients with Huntington's Disease. Participants will taper up to this dose as follows: start at 0.25g/kg/d for 1 week, then take 0.5g/kg/d for 1 week, then take 1g/kg/d and stay on this dose for the duration of the study. Triheptanoin will be administered orally with food or by gastrostomy tube over 3 divided doses (breakfast, lunch, and dinner). If at any point after week 1 a participant does not appear to be tolerating their current dose, it will be reduced by 0.25g/kg/d. If they cannot tolerate the starting dose of 0.25g/kg/d, the treatment will be discontinued. A dietician will make contact with all participants every month, either in person or by telephone, to try and maximize compliance.

The primary outcome measure is the ALSFRS-R score obtained monthly for all treated participants (in person at screening/baseline, month 1, month 3 and month 6; via telephone at months 2, 4 and 5). We will also obtain this measure by phone at months 6 and 12 of the extension. For all enrolled PALS in Groups 1 and 2, we will compare the slope of ALSFRS-R progression before enrollment to the slop of ALSFRS-R progression during the trial. ALSFRS-R is a quickly administered (five minute) ordinal rating scale (ratings 0-4) used to determine patients' assessments of their capability and independence in 13 functional activities. All 13 activities are relevant in ALS. Initial validity was established in ALS patients by documenting that their change in ALSFRS-R scores, which correlated with change in strength over time, was closely associated with quality of life measures, and predicted survival. The test-retest reliability is greater than 0.88 for all 13 itemsactivities. The ALSFRS-R declines linearly with time over a wide range during the course of ALS. The minimum clinically significant change in this scale is said to be 20%. The measure can be reliably conducted over the phone.

Secondary outcome measures include:

MR Spectroscopy NAA/Cr ratio in motor cortex will be measured at screening/baseline and 1 month time points. This measure declines over time in patients with ALS. This measure can respond to treatment; it was shown to improve over 3 weeks in patients with ALS on riluzole compared to a group that was not on this treatment. We will compare the MR spectroscopy changes over 1 month in Group 1 to the MR spectroscopy changes over 1 month in Group 2.

A Serum and Urine Biomarker Panel will be obtained at screening/baseline, 1 month and 6-month time points and analyzed using liquid chromatography/tandem mass spectrometry. Laboratory, pathologic, and epidemiologic evidence clearly supports the hypothesis that oxidative stress is central in the ALS pathogenic process, particularly in genetically susceptive individuals. Oxidative stress biomarkers in cerebrospinal fluid, plasma, and urine are elevated, suggesting that abnormal oxidative stress is generated outside of the central nervous system. Magnitude of lipid peroxidation, measured as non-enzymatic oxidation products of arachidonic acid, F2-isoprostanes, appears the most obvious oxidative stress marker. We will measure urine F2-isoprostane metabolites (class III: iPF2α-III, and 2,3-dinor iPF-2alpha-III, class VI: iPF-2alpha-VI, and 8,12-iso-iPF-2alpha-VI), urine creatinine, and serum and urine glutamate, a-keto-glutarate, NADH, coenzyme A levels in all treated participants and healthy controls at screening/baseline, month 1 and month 6 time points. We will compare the biomarker changes at different times points across between Groups 1, 2 and 3.

For safety monitoring:, concomitant medications, vital signs, weight, physical exam and safety labs (CBC, CMP, Lipid Profile, GGT, LFT and pregnancy testing for sexually active females with child bearing potential) will be measured at screening/baseline, 1 month, 3 month, and 6-month time points. Adverse events will be monitored continuously throughout the study, as described in Section 5.1.

The primary statistical analysis is the slope of the revised ALS functional rating scale (ALSFRS-R) during treatment compared to pre-treatment. Pre-treatment slope for each participant will be estimated as follows: (48-enrollment ALSFRS-R)/months since symptom onset. This frequently used "pre-slope" method is simple and inexpensive, and can predict disease progression as well as more complicated and expensive tools, at least for periods of less than 1 year.

Arms:
arm 1: Standard care for 1 month, then standard care and Triheptanoin for 5 months. arm 2: Standard care and Triheptanoin for 6 months. arm 3: Healthy controls for biomarkers

Interventions: intervention 1: Triheptanoin
Intervention descriptions: intervention 1: Triheptanoin is a medium chain triglyceride (MCT) that can improve mitochondrial function and energy production and therefore has potential for slowing ALS progression. Indeed, triheptanoin slowed motor neuron loss and delayed the onset of weakness in a mutant SOD1 model of ALS. The Triheptanoin we will use is a colorless to light yellow oil. The target triheptanoin dose for this study is 1g/kg/d. This target dose was selected because it was safe and tolerable and altered brain MR spectroscopy in patients with Huntington's Disease.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
A Pilot Trial of Triheptanoin for People with Amyotrophic Lateral Sclerosis (PALS) 
 
NCT03506425 
Duke IRB Number: Pro00092250 
 
 
Protocol Version 1.3 
December 14, 2017 
 
Richard Bedlack, MD, PhD 
Associate Professor of Neurology 
DUKE UNIVERSITY MEDICAL CENTER 
 
 


Triheptanoin in PALS 
Richard Bedlack, MD, PhD 
2 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ..................................................................................................2 
1 
PURPOSE/HYPOTHESES .......................................................................................3 
1.1 
Purpose....................................................................................................................3 
1.2 
Primary Hypothesis ...............................................................................................3 
1.3 
Secondary Hypotheses ...........................................................................................3 
2 
BRIEF BACKGROUND ............................................................................................3 
3 
DESIGN & PROCEDURES ......................................................................................3 
3.1 
Design Overview.....................................................................................................3 
3.2 
Study Population ....................................................................................................4 
3.3 
Treatment Regimen ...............................................................................................5 
3.4 
Trial Procedures and Assessments .......................................................................5 
3.5 
Outcome Measures.................................................................................................7 
3.5.1 
Primary Outcome Measure .............................................................................7 
3.5.2 
Secondary Outcome Measures........................................................................7 
3.6 
Statistical Analysis .................................................................................................8 
4 
STUDY DRUG ............................................................................................................9 
5 
SAFTEY & ADVERSE EVENTS .............................................................................9 
5.1 
Adverse Events Monitoring ..................................................................................9 
5.1.1 
Reporting of Serious Adverse Events ...........................................................10 
5.2 
Data & Safety monitoring ...................................................................................15 
5.3 
Good Clinical Practices and Human Subjects Protection Training ................15 
6 
DATA COLLECTION AND MANAGEMENT ....................................................15 
6.1 
Database ................................................................................................................15 
6.2 
Data Handling and Record Keeping ..................................................................15 
6.3 
Confidentiality and Storage ................................................................................15 
7 
REFERENCES .........................................................................................................15 


Triheptanoin in PALS 
Richard Bedlack, MD, PhD 
3 
 
1 PURPOSE/HYPOTHESES 
1.1 
Purpose 
The purpose of this pilot study is to determine if Triheptanoin is safe and tolerable in people with 
ALS, and if it is associated with any promising changes in a clinical measure of disability or 
biomarkers of cellular energetics or oxidative stress. 
1.2 
Primary Hypothesis 
The primary hypothesis is that Triheptanoin is associated with at least a 20% slowing in disability 
progression as measured by revised ALS functional rating scale (ALSFRS-R) in people with 
amyotrophic lateral sclerosis (PALS). 
1.3 
Secondary Hypotheses 
Secondary hypotheses are as follows: 
1. Triheptanoin favorably alters MR spectroscopy in PALS  
2. Triheptanoin favorably alters serum and urinary biomarkers of mitochondrial function and 
oxidative stress in PALS 
3. Triheptanoin is safe and well tolerated in PALS. 
2 BRIEF BACKGROUND 
Amyotrophic Lateral Sclerosis (ALS) is a degenerative motor neuron disease characterized by 
rapidly progressive disability and shortened survival (1).  PALS lose about a point per month on a 
48-point functional rating scale, and their median survival is 3 years from symptom onset (2).  
While symptomatic care has improved, there remains no treatment that can meaningfully slow 
ALS progression or prolong survival (1).   
The causes of ALS are largely unknown.  However, mitochondrial dysfunction, resulting in 
impaired energy production, oxidative stress and apoptosis, may play a key role in ALS 
progression (3).  Triheptanoin can improve mitochondrial function and energy production and 
therefore has potential for slowing ALS progression (reviewed in reference 3).  Indeed, 
triheptanoin slowed motor neuron loss and delayed the onset of weakness in a mutant SOD1 model 
of ALS (4). 
3 DESIGN & PROCEDURES 
3.1 
Design Overview 
This is an open label, prospective cohort study of 10 PALS from the Duke ALS Clinic (5).  The 
first 5 enrolled PALS (Group 1) will receive standard ALS care for the first month, then standard 
care plus Triheptanoin for the next 5 months.  The next 5 enrolled PALS (Group 2) will receive 
standard ALS care plus Triheptanoin for 6 months (Figure 1).  All Group 1 and Group 2 PALS 
who complete this 6-month study will have an option for Triheptanoin treatment extension for an 


Triheptanoin in PALS 
Richard Bedlack, MD, PhD 
4 
 
additional 12 months.  In addition to the PALS, there will also be 5 healthy controls enrolled 
(Group 3), people that do not have ALS or any other neurodegenerative disease).  These 
participants will not receive any treatment; the only outcome measure they will complete is serum 
and urine biomarker testing at screening/baseline, month 1 and month 6 (Figure 1). 
 
Figure 1: Study Treatment Schema 
Human trials with Triheptanoin have demonstrated an excellent safety profile, with only rare 
associated gastrointestinal side effects (see the provided copy of Ultragenyx’s Investigator’s 
Brochure (IB) and references 6-9).  However, it has never been studied in PALS.  To mitigate the 
risks of rare gastrointestinal side effects, all our participants will be followed by a nutritionist for 
the duration of this study. 
3.2 
Study Population 
Participants will be patients in the Duke ALS Clinic that meet the following criteria. 
Inclusion: 
1. Lab supported probable or more definite ALS by El Escorial Criteria 
2. Age greater than or equal to 18 years 
3. Willing and able to provide informed consent 
4. On riluzole at a stable dose for at least 30d or not taking this 
5. On Radicava at a stable dose for at least 30d or not taking this 
6. Life expectancy at least 6 months 


Triheptanoin in PALS 
Richard Bedlack, MD, PhD 
5 
 
7. Currently managed on a reasonably stable diet, avoidance of fasting, carnitine or 
medium chain triglyceride (MCT) oils 
8. Must stop any other experimental ALS treatment for at least 30 days prior to screening 
9. If sexually active, must agree to use contraceptive or abstinence for duration of 
treatment with triheptanoin 
10. Females of child bearing age must have negative pregnancy test at screening 
Exclusion: 
1. Unwilling or unable to provide informed consent 
2. Previous intolerance or adverse reaction to triheptanoin or MCT 
3. Conditions that will prohibit MRI scanning (metal in eye, some surgical implants, 
claustrophobia, inability to lie supine) 
4. Have any other co-morbid conditions that in the opinion of the study investigator, 
places the participant at increased risk of complications, interferes with study 
participation or compliance, or confounds study objectives 
There will also be 5 healthy controls (adults without ALS or any other neurodegenerative disease) 
enrolled. 
3.3 
Treatment Regimen 
There will be 2 treatment Groups (Figure 1). Five PALS (Group 1) will be on standard care for 1 
month, then standard care and Triheptanoin for 5 months.   Five PALS (Group 2) will be on 
standard care and Triheptanoin for 6 months.  The rationale for delaying triheptanoin treatment in 
one group is to look for differences in MR spectroscopy related to treatment at the 1 month time 
point.  The target triheptanoin dose for this study is 1g/kg/d.  This target dose was selected because 
it was safe and tolerable and altered brain MR spectroscopy in patients with Huntington’s Disease 
(10).  Participants will taper up to this dose as follows: start at 0.25g/kg/d for 1 week, then take 
0.5g/kg/d for 1 week, then take 1g/kg/d and stay on this dose for the duration of the study. 
Triheptanoin will be administered orally with food or by gastrostomy tube over 3 divided doses 
(breakfast, lunch, and dinner).  If at any point after week 1 a participant does not appear to be 
tolerating their current dose, it will be reduced by 0.25g/kg/d.  If they cannot tolerate the starting 
dose of 0.25g/kg/d, the treatment will be discontinued.  A dietician will make contact with all 
participants every month, either in person or by telephone, to try and maximize compliance.  All 
PALS in Groups 1 and 2 who complete the 6-month trial, regardless of their MR spectroscopy 
results, will have the option for treatment extension for an additional 12 months. 
3.4 
Trial Procedures and Assessments 
The intervention being studied is treatment with Triheptanoin.  The procedures and assessments 
being performed include consent, screening for inclusion and exclusion criteria, dispensing study 
drug for consented patients who pass screening, obtaining vital signs, obtaining demographics and 
disease characteristics, obtaining weight, performing a brief physical and neurological exam, 
adverse event monitoring, review of concomitant medications, safety labs, pregnancy testing, 
ALSFRS-R, MRI spectroscopy, serum and urine biomarkers of energetics and oxidative stress.  


Triheptanoin in PALS 
Richard Bedlack, MD, PhD 
6 
 
The schedule for these procedures are outlined in Table 1, and a description of why they are 
important, are provided in the Outcome Measures in Section 3.5. 
Table 1: Schedule of Events for Group 1 and 2 
 
Screening/ 
Baseline 
Visit 
Month 
1 Visit 
Month 
2 Phone 
Call 
Month 
3 Visit 
Month 
4 
Phone 
Call 
Month 
5 
Phone 
Call 
Month 
6 Visit 
Extension 
Month 6 and 
12 
Phone 
Calls 
Consent 
X 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
X 
 
 
 
 
 
 
 
Dispense Drug 
(Group 
2 
only) 
X 
 
X 
 
 
X 
 
Vitals 
X 
X 
 
X 
 
 
X 
 
Demographics and 
Disease 
Characteristics 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
 
X 
 
Physical Exam 
X 
X 
 
X 
 
 
X 
 
Adverse 
Event 
Monitoring* 
X 
X 
X 
X 
X 
X 
X 
X 
Con Meds 
X 
X 
X 
X 
X 
X 
X 
 
Neuro Exam 
X 
X 
 
X 
 
 
X 
 
Safety Labs 
X 
X 
 
X 
 
 
X 
 
Pregnancy Test 
X 
X 
 
 
 
 
X 
 
ALSFRS-R 
X 
X 
X 
X 
X 
X 
X 
X 
MRS 
X 
X 
 
 
 
 
 
 
Serum and Urine 
Biomarkers 
X 
X 
 
 
 
 
X 
 


Triheptanoin in PALS 
Richard Bedlack, MD, PhD 
7 
 
 
Screening/ 
Baseline 
Visit 
Month 
1 Visit 
Month 
2 Phone 
Call 
Month 
3 Visit 
Month 
4 
Phone 
Call 
Month 
5 
Phone 
Call 
Month 
6 Visit 
Extension 
Month 6 and 
12 
Phone 
Calls 
Dietician Contact 
(may be in person 
or telephone) 
X 
X 
X 
X 
X 
X 
X 
 
*Adverse event screening will be captured throughout the protocol and the extension period, and 
continue for an additional 4 weeks following the last dose of study medication. 
Table 2: Schedule of Events for Group 3 
 
Screening/Baseline Visit 
Month 1 Visit 
Month 6 Visit 
Consent 
X 
 
 
Serum and Urine Biomarkers 
X 
X 
X 
3.5 
Outcome Measures 
3.5.1 
Primary Outcome Measure 
The primary outcome measure is the ALSFRS-R score obtained monthly for all treated participants 
(in person at screening/baseline, month 1, month 3 and month 6; via telephone at months 2, 4 and 
5).   We will also obtain this measure by phone at months 6 and 12 of the extension.  For all 
enrolled PALS in Groups 1 and 2, we will compare the slope of ALSFRS-R progression before 
enrollment to the slop of ALSFRS-R progression during the trial (see Section 3.6 below).  
ALSFRS-R is a quickly administered (five minute) ordinal rating scale (ratings 0-4) used to 
determine patients' assessments of their capability and independence in 13 functional activities.  
All 13 activities are relevant in ALS.  Initial validity was established in ALS patients by 
documenting their change in ALSFRS-R scores, which correlated with change in strength over 
time, was closely associated with quality of life measures, and predicted survival (2,11,12). The 
test-retest reliability is greater than 0.88 for all 13 activities. The ALSFRS-R declines linearly with 
time over a wide range during the course of ALS. The minimum clinically significant change in 
this scale is said to be 20% (2,11-13).  The measure can be reliably conducted over the phone (13).   
3.5.2 
Secondary Outcome Measures 
Secondary outcome measures include: 
MR Spectroscopy NAA/Cr ratio in motor cortex will be measured at screening/baseline and 1 
month time points.  This measure declines over time in patients with ALS (14-17).  This measure 
can respond to treatment; it was shown to improve over 3 weeks in patients with ALS on riluzole 
compared to a group that was not on this treatment (18).  We will compare the MR spectroscopy 
changes over 1 month in Group 1 to the MR spectroscopy changes over 1 month in Group 2.   


Triheptanoin in PALS 
Richard Bedlack, MD, PhD 
8 
 
A Serum and Urine Biomarker Panel will be obtained at screening/baseline, 1 month and 6-month 
time points and analyzed using liquid chromatography/tandem mass spectrometry.  Laboratory, 
pathologic, and epidemiologic evidence clearly supports the hypothesis that oxidative stress is 
central in the ALS pathogenic process, particularly in genetically susceptive individuals (19). 
Oxidative stress biomarkers in cerebrospinal fluid, plasma, and urine are elevated, suggesting that 
abnormal oxidative stress is generated outside of the central nervous system. Magnitude of lipid 
peroxidation, measured as non-enzymatic oxidation products of arachidonic acid, F2-isoprostanes, 
appears the most obvious oxidative stress marker. We will measure urine F2-isoprostane 
metabolites (class III:  iPF2α-III, and 2,3-dinor iPF-2alpha-III, class VI:  iPF-2alpha-VI, and 8,12-
iso-iPF-2alpha-VI), urine creatinine, and serum and urine glutamate, a-keto-glutarate, NADH, 
coenzyme A levels in all treated participants and healthy controls at screening/baseline, month 1 
and month 6 time points. We will compare the biomarker changes at different time points between 
Groups 1, 2 and 3.   
For safety monitoring: concomitant medications, vital signs, weight, physical exam and safety labs 
(CBC, CMP, Lipid Profile, GGT, LFT and pregnancy testing for sexually active females with child 
bearing potential) will be measured at screening/baseline, 1 month, 3 month, and 6-month time 
points.  Adverse events will be monitored continuously throughout the study, as described in 
Section 5.1. 
3.6 
Statistical Analysis 
The primary analysis is the slope of the revised ALSFRS-R during treatment compared to pre-
treatment.  Pre-treatment slope for each participant will be estimated as follows: (48-enrollment 
ALSFRS-R)/months since symptom onset. This frequently used “pre-slope” method is simple and 
inexpensive, and can predict disease progression as well as more complicated and expensive tools, 
at least for periods of less than 1 year (20). 
Table 3 shows the results for the power analysis assuming that 10 patients are included in the 
clinical trial. The power of a test is defined as probability of the statistical test to reject a false null 
hypothesis, thus it quantifies the ability of a test to detect an effect, if the effect actually exists. In 
Table 3, the power is expressed as a percentage and the standard deviation is given in parenthesis. 
The number of observations were assumed to occur one per month after the beginning of the trial. 
The percentage of change in the slope of ALSRFRS-R as function of time is measured against the 
pre-trial rate of decline. For each combination of slope percentage change and number of 
observations, 1000 samples were randomly generated assuming the following parameters:  
• The ALSFRS-R score at the beginning of the treatment was uniformly distributed in the 
range [2, 40]. 
• The pre-trial slope was log-normally distributed with mean 0.90 (per month), and standard 
deviation 0.27. Thus, the range of pre-trial slopes is approximately [0.25, 3.38]. 
• The measurement error for the ALSRFRS-R was assumed to be normally distributed with 
zero mean and standard deviation 0.7. This way the inter-quartile range is approximately 
[-0.5, 0.5]. 


Triheptanoin in PALS 
Richard Bedlack, MD, PhD 
9 
 
Table 3: Power Analysis Based on 10 Patients.  Power percentage along with standard deviation in parenthesis for 
detecting a change in the slope of ALSFRS-R with respect to time using 10 patients in a clinical trial setting. The 
power is given as function of both the number of observations and the percentage of change in the slope. 
 
4 STUDY DRUG 
Triheptanoin is a medium chain triglyceride (MCT) that can improve mitochondrial function and 
energy production and therefore has potential for slowing ALS progression (reviewed in reference 
3).  Indeed, triheptanoin slowed motor neuron loss and delayed the onset of weakness in a mutant 
SOD1 model of ALS (4).  The Triheptanoin we will use is a colorless to light yellow oil.  The 
target triheptanoin dose for this study is 1g/kg/d.  This target dose was selected because it was safe 
and tolerable and altered brain MR spectroscopy in patients with Huntington’s Disease (10).  
Participants will taper up to this dose as follows: start at 0.25g/kg/d for 1 week, then take 0.5g/kg/d 
for 1 week, then take 1g/kg/d and stay on this dose for the duration of the study. Triheptanoin will 
be administered orally with food or by gastrostomy tube over 3 divided doses (breakfast, lunch, 
and dinner).  If at any point after week 1 a participant does not appear to be tolerating their current 
dose, it will be reduced by 0.25g/kg/d.  If they cannot tolerate the starting dose of 0.25g/kg/d, the 
treatment will be discontinued.  A dietician will make contact with all participants every month, 
either in person or by telephone, to try and maximize compliance.   
Additional details about this drug are available in the accompanying IB. 
5 SAFTEY & ADVERSE EVENTS 
5.1 
Adverse Events Monitoring   
All adverse events (AEs), whether observed by the Investigator, elicited from the participant or 
volunteered by the participant, and whether ascribed to the drug or not, will be recorded.  This will 
include the following: a brief description of the event, the date of onset, the date of resolution, the 
duration and type of the event, the severity, contributing factors and any action taken with respect 
to the study drug. This recording will commence following informed consent, and with the 
initiation of protocol-specific procedures and continue at each study visit or telephone contact until 
4 weeks following the last study related visit. 


Triheptanoin in PALS 
Richard Bedlack, MD, PhD 
10 
 
For each adverse event, the relationship to the study drug will be recorded as one of the choices 
on the following scale: 
DEFINITE 
Causal relationship is certain (i.e., the temporal relationship between drug 
exposure and the adverse event onset/course is reasonable, there is a clinically compatible 
response to de-challenge, other causes have been eliminated and the event must be 
definitive pharmacologically or phenomenologically using a satisfactory re-challenge 
procedure if necessary). 
PROBABLE High degree of certainty for causal relationship (i.e., the temporal 
relationship between drug exposure and the adverse event onset/course is reasonable, there 
is a clinically compatible response to de-challenge [re-challenge is not required] and other 
causes have been eliminated or are unlikely). 
POSSIBLE 
Causal relationship is uncertain (i.e., the temporal relationship between drug 
exposure and the adverse event onset/course is reasonable or unknown, de-challenge/re-
challenge information is either unknown or equivocal and while other potential causes may 
or may not exist, a causal relationship to the study drug does not appear probable). 
UNLIKELY Not reasonably related, although a causal relationship cannot be ruled out 
(i.e., while the temporal relationship between drug exposure and the adverse event 
onset/course does not preclude causality, there is a clear alternate cause that is more likely 
to have caused the adverse event than the study drug). 
NOT RELATED 
No possible relationship (i.e., the temporal relationship between 
drug exposure and the adverse event onset/course is unreasonable or incompatible, or a 
causal relationship to study drug is implausible). 
The severity of each adverse event must be recorded as one of the choices on the following scale: 
MILD  
 
No limitation of usual activities 
MODERATE  
Some limitation of usual activities 
SEVERE 
 
Inability to carry out usual activities 
The expectedness of an AE must be indicated when reporting adverse events.  An unexpected 
adverse event is any adverse experience for which the specificity or severity of the event is not 
consistent with the current IB.   
5.1.1 
Reporting of Serious Adverse Events 
A serious adverse drug event (SAE) is defined as any adverse event that occurs during the study 
that results in any of the following outcomes: death, a life-threatening adverse event (i.e., the 
participant was at immediate risk of death from the event as it occurred; does not include an event, 
that had it occurred in a more severe form, might have caused death), inpatient hospitalization or 
prolongation of existing hospitalization (hospitalizations scheduled before enrollment for an 
elective procedure or treatment of a pre-existing condition which has not worsened during 


Triheptanoin in PALS 
Richard Bedlack, MD, PhD 
11 
 
participation in the study will not be considered a serious adverse event), a persistent or significant 
disability/incapacity (substantial disruption of one's ability to conduct normal life functions), a 
congenital anomaly/birth defect, a medically important event or required medical intervention to 
avoid one of the above outcomes.  In addition to the above procedures for AEs, all SAEs will be 
reported to the IRB within 24 hours of recording.  All serious adverse event information will be 
followed until resolution or an appropriate end point is reached. This may involve contacting other 
clinicians responsible for the participant’s care to obtain information on diagnoses, investigations 
performed and treatment given. 
Institution and Sponsor-Investigator are responsible for the identification, collection, reporting and 
documentation of SAEs in patient(s) participating in the Protocol.  Institution and Sponsor-
Investigator are responsible for complying with all Applicable Laws concerning the reporting of 
Suspected Unexpected Serious Adverse Reactions (SUSARs) to the IRB and regulatory authorities 
(FDA), in accordance with 21 CFR 312.32, in connection with the Protocol. Notwithstanding the 
foregoing, Institution and Sponsor-Investigator shall comply with IRB reporting instructions and 
all Applicable Laws regarding SAE reporting.  
The Sponsor-Investigator shall collect AEs and SAEs for patient(s) receiving Investigational 
Product at the Institution as per protocol. Sponsor-Investigator shall record seriousness, causality 
and expectedness assessments for each AE as per Institution’s policies. All SAEs provided to 
Ultragenyx must have the Sponsor-Investigator’s assessment of seriousness, causality and 
expectedness. Events not listed in the Investigator Brochure (IB) are considered “unexpected” and 
events listed in the IB are considered “expected.” The Institution and/or Sponsor-Investigator is 
responsible for determining the reportability of each assessed SAE. All SAEs considered by the 
Sponsor-Investigator as unexpected per the IB, and Investigational Product related, must be 
reported as a SUSAR by the Sponsor-Investigator to the FDA and IRBs in accordance with 
Applicable Laws.  
All SUSARs shall be reported to FDA and Ultragenyx by completing and submitting MedWatch 
3500A form.  Safety reports must be as complete as possible, at minimum including the SAE 
term(s), patient identifier, seriousness criteria, date of event onset, causality and expectedness 
assessment between each reported SAE term and Investigational Product, and name of the reporter 
(Sponsor-Investigator). Information not available at the time of the initial report shall be 
documented on a follow-up report and submitted to Ultragenyx (and/or regulatory authorities, 
IRBs, accordingly) as specified in Table 4.  Additional information shall include SAE stop date(s), 
outcome for each reported SAE, dates when Investigational Product was first received and the last 
dose prior to event onset, and action taken with Investigational Product as a result of the SAE. If 
applicable, the Institution and/or Sponsor-Investigator protocol number shall be included in all 
MedWatch Form 3500A or CIOMS I reports. 
SAEs with fatal and/or life-threatening outcomes occurring during treatment, regardless of 
causality or expectedness shall be reported to Ultragenyx within 7 calendar days of event 
knowledge. In addition, SAEs meeting SUSAR criteria, as defined by Applicable Laws and 
regulations, occurring during treatment, shall be reported to FDA and Ultragenyx within 15 
calendar days of event knowledge. The Sponsor-Investigator must also notify the IRB of the SAEs 
in accordance with IRB requirements and Applicable Laws and regulations.  


Triheptanoin in PALS 
Richard Bedlack, MD, PhD 
12 
 
Institution and/or Sponsor-Investigator shall submit all initial and follow-up SUSAR reports to the 
FDA, IRBs, and Ultragenyx within regulatory defined timeframes. Final versions of the initial 
fatal and/or life-threatening SUSAR reports will be submitted as soon as possible but no later than 
7-calendar days of first knowledge of the event, and follow-up information will be submitted 
within an additional 8-calendar days to the FDA, IRB and Ultragenyx. All other SUSARs will be 
submitted to the FDA, IRB and Ultragenyx within 15-calendar days of first knowledge of the 
event.  Reports shall not be delayed due to incomplete information, which can be supplied as 
follow-up at a later time.  Sponsor-Investigator shall record non-serious adverse events per 
Institution’s clinical procedures. Where there is any doubt or debate relating to whether an AE is 
serious or non-serious, the AE shall be treated as an SAE until information is received to clarify 
seriousness. Sponsor-Investigator shall cooperate with Ultragenyx in any request for information 
on SAE reporting related to the Protocol. Ultragenyx will not be responsible for reporting safety 
information from treatment of patient(s) by Sponsor-Investigator or Institution to the Health 
Authorities. 
The following timeframes shall apply to both initial and follow-up reports unless otherwise 
specified:  
Sponsor-Investigator shall send to Ultragenyx final copies of initial and follow-up SAE reports 
within the timeframes specified in Table 4 using FDA MedWatch Form 3500A.  
Table 4: Reporting Timeframe from Sponsor-Investigator to Ultragenyx 
Type of Report 
Reporting 
Timeframe 
from  Sponsor-Investigator 
to Ultragenyx 
Format 
Suspected 
Unexpected 
Serious Adverse Reactions – 
Fatal and Life-threatening 
Final report no later than 7 
calendar 
days 
from 
Sponsor-Investigator 
event knowledge with an 
additional 8 calendar days 
for follow-up report.  
FDA 
MedWatch 
3500A) 
 
Suspected 
Unexpected 
Serious Adverse Reactions – 
other serious criteria  
Final report no later than 
15 
calendar 
days 
of 
Sponsor-Investigator 
event knowledge.  
FDA 
MedWatch 
3500A 
Suspected 
Unexpected 
Serious Adverse Reactions – 
Follow-up reports   
No later than 15 calendar 
days 
after 
Sponsor-
Investigator 
receipt 
of 
follow-up information (see 
follow-up 
requirements 
above 
for 
fatal/life-
threatening SUSAR)  
FDA 
MedWatch 
3500A 
Non-SUSAR 
SAEs 
- 
regardless of relatedness to 
the Product  
No later than 30 calendar 
days 
from 
Sponsor-
Investigator 
event 
knowledge  
FDA 
MedWatch 
3500A and SAE line 
listing  


Triheptanoin in PALS 
Richard Bedlack, MD, PhD 
13 
 
Type of Report 
Reporting 
Timeframe 
from  Sponsor-Investigator 
to Ultragenyx 
Format 
Annual Safety Report 
Provided in parallel with 
submission to regulatory 
authorities 
Annual Safety Report 
Ultragenyx shall provide the Institution and/or Sponsor-Investigator copies of SUSARs received 
from other clinical trials or expanded access using the same Investigational Product as specified 
in Table 5. 
Table 5: Reporting Timeframe from Ultragenyx to Institution and/or Sponsor-Investigator 
Type of Report 
Reporting 
Timeframe 
from 
Ultragenyx 
to 
Institution 
and/or 
Sponsor-Investigator 
Format 
Suspected 
Unexpected 
Serious Adverse Reactions – 
Fatal and Life-threatening* 
No later than 7 calendar 
days 
from 
Ultragenyx 
event knowledge 
FDA 
MedWatch 
3500A  
Suspected 
Unexpected 
Serious Adverse Reactions – 
other serious criteria* 
No later than 15 calendar 
days 
from 
Ultragenyx 
event knowledge 
FDA 
MedWatch 
3500A 
Suspected 
Unexpected 
Serious Adverse Reactions – 
Follow-up reports* 
No later than 15 calendar 
days 
after 
Ultragenyx 
receipt 
of 
follow-up 
information 
FDA 
MedWatch 
3500A 
Investigational 
Product 
Investigator 
Brochure 
(including 
safety 
attachments, as appropriate) 
Within 15 calendar days 
of final update  
Email 
to 
Sponsor-
Investigator  
*SUSARs from Ultragenyx-sponsored studies using the same Investigational Product (cross-
reporting to Sponsor-Investigators) 
Should Ultragenyx require additional information on a SAE, Ultragenyx may send a request to the 
Institution and Sponsor-Investigator for follow-up as appropriate. Institution and Sponsor-
Investigator shall use reasonably diligent efforts to conduct follow up activities on SAE reports in 
accordance with their standard operating procedures and in compliance with all Applicable Laws.  
Institution and Sponsor-Investigator shall transmit to Ultragenyx the information required pursuant 
to the above provisions by facsimile, e-mail or other agreed-upon electronic means. If the volume 
of pages is deemed too large for reasonable electronic transmission, the information will be sent 
by expedited courier service. 
All SUSARs and SAEs shall be documented and provided to Ultragenyx/designee using the FDA 
MedWatch Form 3500A or CIOMS I form (non-US) within the timeframes set forth in Table 4.  


Triheptanoin in PALS 
Richard Bedlack, MD, PhD 
14 
 
Contact information:  
Ultragenyx Pharmaceutical/designee 
eFax: 1.415.930.4033 
email: Ultragenyx@PrimeVigilance.com 
For other safety related correspondence including providing of annual safety reports:  
Contact information:  
Ultragenyx Drug Safety and Pharmacovigilance 
eFax: 415.299.8985 or 1.888.866.5771 
email: DrugSafety@ultragenyx.com    
The Sponsor-Investigator is also responsible for providing Ultragenyx all final SAE and SUSAR 
reports submitted to regulatory authorities via the contact information listed above. The report 
must be completed on a FDA MedWatch Form 3500A. Ultragenyx reserves the right to review 
SUSAR reports, SAE reports or source documents pertaining to Protocol safety reports in response 
to any regulatory authority inquiries received.  
SUSARs shall not be considered addendums to the IB until a formal update to the IB is made by 
Ultragenyx. 
As per Applicable Laws, the Institution and/or Sponsor-Investigator are responsible for the 
development and submission of annual safety reports to regulatory health authorities and IRBs as 
it pertains to the overall conduct of the specific Protocol. The Institution and/or Sponsor-
Investigator shall provide Ultragenyx a copy of the annual safety report in parallel to its submission 
to regulatory authorities.  
Ultragenyx shall provide the Institution and/or Sponsor-Investigator a copy of the IB and any 
revisions within the specified timeframe (Table 5). 
Ultragenyx will be responsible for the conduct of surveillance and safety signal detection activity 
using the Global Safety Database and ad-hoc reports in accordance with Ultragenyx sponsored 
study procedures and will notify Sponsor-Investigator of safety signals that do, or may, affect the 
safety profile of the Investigational Product, taking into consideration the urgency of the matter 
and the Applicable Laws.  
Ultragenyx and Sponsor-Investigator shall promptly inform each other of all adverse event 
information relating to Investigational Product, including but not limited to, safety issues that 
either party becomes aware of or material safety-related regulatory queries from regulatory 
authorities taking into consideration the urgency of the matter and the Applicable Laws. The 
Sponsor-Investigation will submit an IND Safety Report for any SUSARs, according to 21 CFR 
312.32, when informed of such event by Ultragenyx.  Ultragenyx may request assistance from 
Sponsor-Investigator to evaluate and investigate such safety information and Sponsor-Investigator 
undertakes to use reasonably diligent efforts to promptly investigate and respond to Ultragenyx's 
requests.   


Triheptanoin in PALS 
Richard Bedlack, MD, PhD 
15 
 
Sponsor-Investigator shall be solely responsible for regulatory submissions of AEs and SAEs in 
regards to the Sponsor-Investigator’s regulatory health authority approval and IRB in accordance 
with the Applicable Laws. 
5.2 
Data & Safety monitoring  
Adverse events will be continuously tracked throughout the study as described above and below.  
There is no formal safety monitoring plan or DSMB, nor are there any formal stopping rules.  
Patients who do not tolerate triheptanoin (as described in Section 3.3) will be encouraged to 
continue in the protocol off-treatment.  PI will review and sign off on all adverse events and 
promptly report these to the IRB. 
5.3 
Good Clinical Practices and Human Subjects Protection Training  
The investigator and coordinator involved with the conduct of this study will be certified in Good 
Clinical Practices (GCP) and Human Subjects Protection training. Human Subjects Protection 
training certification will be obtained by completing approved training, such as the online 
computer based training offered by the NIH Office of Human Subjects Research 
(http://ohsr.od.nih.gov).  
6 DATA COLLECTION AND MANAGEMENT 
6.1 
Database 
Data will be collected on paper case report forms.  Each participant’s paper case report forms will 
be stored in a paper binder.  Data from paper forms will be transferred to electronic case report 
forms (eCRFs) in a newly created RedCap electronic database. 
6.2 
Data Handling and Record Keeping   
The Site Investigator (SI) is responsible to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported.  Data reported in the eCRF derived from paper case report forms 
should be consistent with these and discrepancies should be explained. 
6.3 
Confidentiality and Storage 
Participants will be assigned unique study identification numbers.  All forms and samples will be 
identified only by these numbers.   The identification key and all study binders will be kept in a 
locked office.  The study database will be password protected, and stored on a password protected 
computer.  No identifiable information on study participants will leave Duke University. 
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