- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03506425
A Pilot Trial of Triheptanoin for People With Amyotrophic Lateral Sclerosis (PALS)
Study Overview
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
-
-
North Carolina
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Durham, North Carolina, United States, 27705
- Duke University
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Lab supported probable or more definite ALS by El Escorial Criteria
- Age greater than or equal to 18 years
- Willing and able to provide informed consent
- On riluzole at a stable dose for at least 30d or not taking this
- On Radicava at a stable dose for at least 30d or not taking this
- Life expectancy at least 6 months
- Currently managed on a reasonably stable diet, avoidance of fasting, carnitine or medium chain triglyceride (MCT) oils
- Must stop any other experimental ALS treatment for at least 30 days prior to screening
- If sexually active, must agree to use contraceptive or abstinence for duration of treatment with triheptanoin
- Females of child bearing age must have negative pregnancy test at screening
Exclusion Criteria:
- Unwilling or unable to provide informed consent
- Previous intolerance or adverse reaction to triheptanoin or MCT
- Conditions that will prohibit MRI scanning (metal in eye, some surgical implants, claustrophobia, inability to lie supine)
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NON_RANDOMIZED
- Interventional Model: SINGLE_GROUP
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Group 1
Standard care for 1 month, then standard care and Triheptanoin for 5 months.
|
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.
|
EXPERIMENTAL: Group 2
Standard care and Triheptanoin for 6 months.
|
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.
|
NO_INTERVENTION: Group 3
Healthy controls for biomarkers
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
ALS Functional Rating Scale-revised Version (ALSFRS-R) Slope
Time Frame: baseline, 6 months
|
Amyotrophic lateral sclerosis functional rating scale-revised version (ALSFRS-R) is used to determine patients' assessments of their capability and independence in 12 functional activities.
All 12 activities are relevant in ALS and each is scored between 0 (no function at all) and 4 (normal function).
Thus the overall score for this measure can range from 0 to 48, with higher scores indicating more normal function.
The test-retest reliability is greater than 0.88 for all 12 items/activities.
The ALSFRS-R declines linearly with time over a wide range during the course of ALS and the minimum clinically significant change in this scale is said to be 20%.
The primary analysis in this study is the slope of the 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.
|
baseline, 6 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in NAA/Cr Ratio From Motor Cortex as Measured by Magnetic Resonance Spectroscopy
Time Frame: baseline, 6 months
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Effects of time, Triheptanoin on NAA/Cr (N-acetylaspartate/creatine) ratio from motor cortex
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baseline, 6 months
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Change in Urine Isoprostane Levels, an Oxidative Stress Marker
Time Frame: baseline, 1 month
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Effects of ALS and/or Triheptanoin on urine isoprostane levels (a marker of oxidative stress) at month 1
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baseline, 1 month
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Richard S Bedlack, MD PhD, Duke ALS Clinic
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ACTUAL)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- Pro00092250
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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