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

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.

Study Overview

• Status: Completed
• Conditions: Huntington Disease
• Intervention / Treatment: Drug: Placebo; Drug: Triheptanoin oil

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • Département de Génétique
• Netherlands
  • Leiden, Netherlands, 2300RC
    • Department of Neurology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo group; 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; Safflower oil orally administered at 1g/kg/day
ACTIVE_COMPARATOR: Triheptanoin group; 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; Triheptanoin oil orally administered at 1g/kg/day

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Institut National de la Santé Et de la Recherche Médicale, France
• Collaborators: Ultragenyx Pharmaceutical Inc

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 29, 2015
• Primary Completion (ACTUAL): December 3, 2019
• Study Completion (ACTUAL): December 3, 2019

Study Registration Dates

• First Submitted: May 12, 2015
• First Submitted That Met QC Criteria: May 20, 2015
• First Posted (ESTIMATE): May 25, 2015

Study Record Updates

• Last Update Posted (ACTUAL): August 25, 2021
• Last Update Submitted That Met QC Criteria: August 24, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Dyskinesias; Heredodegenerative Disorders, Nervous System; Dementia; Cognition Disorders; Chorea; Huntington Disease
• Other Study ID Numbers: C14-62