A comparative phase2 study assessing the efficacy of triheptanoin, an anaplerotic therapy in Huntington's Disease (HD)

Huntington*s disease (HD) is an autosomal dominant disease characterized by
movement disorders (chorea), behavioral, and neuropsychiatric disturbances. The
clinical features of HD usually emerge in adult life and there is currently no
curative treatment. The only existing treatment approved in HD is Tetrabenazine
which treats irregular movements known as chorea, one of the major symptoms of
HD. No treatment has yet been proven to slow, delay, or correct the course of
the disease. Longitudinal imaging studies showed that caudate atrophy is the
earliest change identified to date in the disease process. It has been shown to
be a more reliable indicator of disease progression than any existing clinical
measures (Tabrizi, 2013). Other studies showed that energy deficit plays a
critical role in the pathogenesis of HD. Specifically, weight loss was
associated with a plasmatic decrease in branched chain amino acids in
premanifest individuals on a high caloric diet (Mochel, 2007) suggesting the
activation of compensatory mechanisms to provide energy substrates to the Krebs
cycle. As a strategy to improve energy metabolism in HD, the following studies
were carried out:
TRIHEP 1 demonstrated the safety and short-term metabolic correction in the
muscle of the use of triheptanoin, an anaplerotic compound providing substrates
to the Krebs cycle (Mochel, 2010). Using 31-Phosphorus Magnetic Resonance
Spectroscopy (31P-MRS), PROMH 1 identified the inorganic
phosphate/phosphocreatine (Pi/PCr) ratio as an outcome measure of brain
metabolic dysfunction in HD patients (Mochel, 2012).
PROMH 2 confirmed the existence of an abnormal energy profile in HD patients,
i.e. abnormal Pi/PCr ratio during brain activation, stable over time
(Adanyeguh, 2015).
TRIHEP 2 tested the benefit of triheptanoin on the 31P-MRS metabolic profile of
the brain and compliance. After one month of treatment, triheptanoin restored a
normal Pi/PCr ratio in HD patients during brain activation (Adanyeguh, 2015).
TRIHEP 3 is a multi-centre (Paris and Leiden) randomized, double-blind,
controlled study recruiting 100 early HD patients. Patients will receive either
triheptanoin or a placebo for 6 months followed by a 6 month open-label phase
with triheptanoin. The expected efficacy of triheptanoin will be measured by
the caudate volume, brain energy metabolism using P-MRS, and clinical outcome
measures

An extension period of 1 year may be proposed to patients who wish to pursue
triheptanoin based on their perception of a possible clinical benefit.

The primary objective of TRIHEP 3 is to evaluate the efficacy of triheptanoin
in (i) increasing the short term energy response in the metabolic profile of
the brain of early affected HD patients, as captured by 31P-MRS, and (ii)
slowing atrophy in the caudate of early affected HD patients as measured with
volumetric magnetic resonance imaging.

The secondary objectives are:
- Sustained restoration of brain energy metabolism after 6 months and 1 year of
treatment.
- Decrease in rate of caudate atrophy after 1 year of treatment.
- To assess the clinical benefit of triheptanoin on motor function in HD
patients using scores on the Unified Huntington*s Disease Rating Scale (UHDRS)
and Total Functional Capacity (TFC).
- To assess the clinical benefit of triheptanoin on cognitive function and
psychiatric symptoms in HD patients using scores on the neuropsychological
battery and the PBA-S.
- To investigate the effect of triheptanoin on quality of life short video's
that will be recorded at the end of the randomized phase and a questionnaire
will be used (SF-36).
- To look for correlations between neuroimaging volumetric parameters, brain
energy profiles and clinical scores, before and after treatment.
- Safety of triheptanoin will be evaluated based on review of adverse events
and changes in clinical labs and physical examination/vital signs.
- Long-term tolerance will be confirmed by clinical exam at study visits and by
patient report during phone calls and home visits.
- Changes in brain energy profiles will be correlated with volumetric measures
and clinical rating scale scores.

TRIHEP3 is a phase 2, multicenter double-blind, randomized, controlled
two-armed study evaluating the efficacy of 1g/kg of body weight triheptanoin
per day versus a placebo for a six month treatment period, followed by a 6
month open-labelled period with all patients treated with triheptanoin. An
extension period of 1 year may be proposed to patients who wish to pursue
triheptanoin based on their perception of a possible clinical benefit. Patiens
who are willing to continue with the triheptanoin oil have to sign a new
informed consent form.

Treatment with triheptanoin or placebo (1g/kg), intake of triheptanoin/placebo
4 times a day (added to a meal) during the first 6 months. Followed by
treatment with triheptanoin during the next 6 months.
The extension phase is a continuation of the open label phase with treatment of
triheptanoin for the duration of 12 months.

Triheptanoin has been well tolerated with no significant safety issues. The
most commonly reported adverse effects are gastro-intestinal distress and
excessive weight gain at high doses.

Burden:
6 visits during 1 year at the Leiden University Medical Centre (LUMC). The
screening visit last approximately 2 hours and all other visits lasts
approximately half a day. Between the hospital visits a nurse will visit the
subject at home 8 times. Furthermore, there will be regularly telephone
contacts by the dietitian and/or other trial team members.

The following procedures will take place during the trial:
Blood samples (5x)
Urine samples (13x)
Pregnancy test (6x)
Dietary Consultation (6x)
MRI (4x)
Medical and neurological exam (5x)
Questionnaires and neuropsychological tests (3x)
Psychiatric evaluation (5x)

After the first 1-year treatment period an extension phase will be proposed to
voluntary patients who wish to pursue triheptanoin based on their perception of
a possible clinical benefit.
The following procedures will take place during the extension phase:
Blood samples (3x)
Urine samples (3x)
Pregnancy test, if applicable (3x)
Dietary Consultation (3x)
MRI (1x)
Medical and neurological exam (3x)
Questionnaires and neuropsychological tests (1x)
Psychiatric evaluation (1x)