A Comparative Phase 2 Study Assessing the Efficacy of Triheptanoin, an Anaplerotic Therapy in Huntington's Disease (TRIHEP3)

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

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

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.

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)

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)

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

Decrease in the progression of the UHDRS United Huntington's Disease Rating Scale after 6 months of treatment

Decrease in the progression of the UHDRS United Huntington's Disease Rating Scale after 12 months of treatment

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

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

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

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

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

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

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

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

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

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

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

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

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).

A standardized quality of life questionnaire, the Short Form-36 Health Survey, will be used after 6 months

A standardized quality of life questionnaire, the Short Form-36 Health Survey, will be used after 12 months

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

Rodrigues FB, Ferreira JJ, Wild EJ. Huntington's Disease Clinical Trials Corner: June 2019. J Huntingtons Dis. 2019;8(3):363-371. doi: 10.3233/JHD-199003.