A Comparative Phase 2 Study Assessing the Efficacy of Triheptanoin, an Anaplerotic Therapy in Huntington's Disease

Study Overview
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Brief Summary
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In the study the investigators plan to include 100 early affected HD patients (5 ≤ UHDRS ≤ 40) in a randomized, double-blind, controlled study in 2 centers (France and the Netherlands). Patients will receive either triheptanoin at 1g/kg of body weight per day (n = 50), or a control oil (n = 50) at 1g/kg of body weight per day for 6 months followed by an open label phase using triheptanoin for another 6 months. Efficacy of triheptanoin will be evaluated by measurements of caudate volume using volumetric magnetic resonance imaging and brain energy metabolism as evaluated by the ratio of inorganic phosphate/phosphocreatine, during visual stimulation, using 31P-MRS. Clinical improvement will be evaluated by UHDRS, TFC, and PBA-S scores as well as performance on the neuropsychological battery; patient quality of life will be evaluated with qualitative research methods after 6 months and with the SF-36 questionnaire before and after treatment; biological tolerance and compliance will be evaluated by routine biochemical blood tests, plasma and urine measurements of triheptanoin oil derivatives and patient report.

Official Title
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A Comparative Phase 2 Study Assessing the Efficacy of Triheptanoin, an Anaplerotic Therapy in Huntington's Disease

Conditions
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Huntington Disease

Intervention / Treatment
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* Drug: Triheptanoin oil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Positive genetic test with CAG repeat length ≥39 in HTT gene At least 18 years of age Signature of informed consent Covered by social security UHDRS score between 5 and 40 Ability to undergo MRI scanning BMI between 18 and 30 Exclusion Criteria: Hypersensitivity to triheptanoin or to one of its excipients Additional major comorbidities History of severe head injury Participation in another therapeutic trial (3 month exclusion period) For women of childbearing age, the absence of two forms of effective contraception (with the exception of those who are abstinent) Pregnancy or breastfeeding Inability to understand information about the protocol Persons deprived of their liberty by judicial or administrative decision Adult subject under legal protection or unable to consent Treatment with tetrabenazine

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo group<br>Subjects will receive safflower oil at 1g/kg/day for 6 months (months 0 - 6) and triheptanoin oil at 1g/kg/day for 6 months (months 7 - 12) | Drug: Placebo<br>* Safflower oil orally administered at 1g/kg/day<br>|
| Active Comparator: Triheptanoin group<br>Subjects will receive triheptanoin oil at 1g/kg/day for 6 months (months 0 - 6) and triheptanoin oil at 1g/kg/day for 6 months (months 7 - 12) | Drug: Triheptanoin oil<br>* Triheptanoin oil orally administered at 1g/kg/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 31-Phosphorus Magnetic Resonance Spectroscopy | An increase in the index of brain energy restoration - as defined by the difference between Pi/PCr ratio during visual stimulation and the mean of Pi/PCr ratio during rest and recovery - using 31P-MRS | 3 months | 
| volumetric magnetic resonance imaging | A decrease in the rate of caudate atrophy, using volumetric MRI | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| motor function after 6 months | Decrease in the progression of the UHDRS United Huntington's Disease Rating Scale after 6 months of treatment | 6 months | 
| motor function after 12 months | Decrease in the progression of the UHDRS United Huntington's Disease Rating Scale after 12 months of treatment | 12 months | 
| Patient autonomy after 6 months | Stability of the Total Functional Capacity (TFC) after 6 months of treatment | 6 months | 
| Patient autonomy after 12 months | Stability of the Total Functional Capacity (TFC) after 12 months of treatment | 12 months | 
| Sustained restoration of brain energy metabolism after 6 months | Sustained restoration of brain energy metabolism using 31P-MRS after 6 months of treatment | 6 months | 
| Sustained restoration of brain energy metabolism after 12 months | Sustained restoration of brain energy metabolism using 31P-MRS after 12 months of treatment | 12 months | 
| Symbol Digit Modalities Test after 6 months | The benefit of triheptanoin on cognitive function will be evaluated after 6 months using a neuropsychological battery including the SDMT (Symbol Digit Modalities Test), a test of visuomotor coordination | 6 months | 
| Symbol Digit Modalities Test after 12 months | The benefit of triheptanoin on cognitive function will be evaluated after 12 months using a neuropsychological battery including the SDMT (Symbol Digit Modalities Test), a test of visuomotor coordination | 12 months | 
| Stroop test after 6 months | The benefit of triheptanoin on cognitive function will be evaluated after 6 months using a neuropsychological battery including the Stroop test, a test evaluating concentration and capacity for inhibition | 6 months | 
| Stroop test after 12 months | The benefit of triheptanoin on cognitive function will be evaluated after 12 months using a neuropsychological battery including the Stroop test, a test evaluating concentration and capacity for inhibition | 12 months | 
| Trail making test after 6 months | The benefit of triheptanoin on cognitive function will be evaluated after 6 months using a neuropsychological battery including the Trail making test, a test to evaluate mental flexibility | 6 months | 
| Trail making test after 12 months | The benefit of triheptanoin on cognitive function will be evaluated after 12 months using a neuropsychological battery including the Trail making test, a test to evaluate mental flexibility | 12 months | 
| Digit span test after 6 months | The benefit of triheptanoin on cognitive function will be evaluated after 6 months using a neuropsychological battery including the Digit span test, a test evaluating attention and working memory | 6 months | 
| Digit span test after 12 months | The benefit of triheptanoin on cognitive function will be evaluated after 12 months using a neuropsychological battery including the Digit span test, a test evaluating attention and working memory | 12 months | 
| psychiatric symptoms after 3 months | The effect of triheptanoin on psychiatric symptoms will be evaluated after 3 months with the PBA-S, an evaluation of problem behaviors associated with HD | 3 months | 
| psychiatric symptoms after 6 months | The effect of triheptanoin on psychiatric symptoms will be evaluated after 6 months with the PBA-S, an evaluation of problem behaviors associated with HD | 6 months | 
| psychiatric symptoms after 9 months | The effect of triheptanoin on psychiatric symptoms will be evaluated after 9 months with the PBA-S, an evaluation of problem behaviors associated with HD | 9 months | 
| psychiatric symptoms after 12 months | The effect of triheptanoin on psychiatric symptoms will be evaluated after 12 months with the PBA-S, an evaluation of problem behaviors associated with HD | 12 months | 
| patients' daily life | The global impact of triheptanoin on patients' daily life will be evaluated at the end of the blinded treatment period using qualitative research methods. To statistically test whether experts classify treated and not treated patients better than could be expected by chance, a permutation test based on a modified version of Fisher's Lady tasting tea procedure will be used (Fischer 1935). | 6 months | 
| quality of life questionnaire after 6 months | A standardized quality of life questionnaire, the Short Form-36 Health Survey, will be used after 6 months | 6 months | 
| quality of life questionnaire after 12 months | A standardized quality of life questionnaire, the Short Form-36 Health Survey, will be used after 12 months | 12 months | 
| Number of adverse events | Safety of triheptanoin will be evaluated based on review of adverse events | 12 months | 
| clinical exam for Long term tolerance | Long-term tolerance will be confirmed by clinical exam at study visits | 12 months | 
| home nurse visits for Long term tolerance | Long-term tolerance will be confirmed by patient report during home nurse visits | 12 months |