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Huntington’s Disease Clinical Trials Corner: June 2019

Abstract

In this edition of the Huntington’s Disease Clinical Trials Corner we expand on the HD-DBS and on the TRIHEP3 trials, and we list all currently registered and ongoing clinical trials in Huntington’s disease.

INTRODUCTION

The Huntington’s Disease Clinical Trials Corner is a regular section devoted to highlighting ongoing and recently completed clinical trials in Huntington’s disease (HD). Clinical trials previously reviewed by the Huntington’s Disease Clinical Trials Corner are listed in Table 1.

Table 1

Clinical trials previously reviewed by the Huntington’s Disease Clinical Trials Corner

Trial nameInterventionEdition
NCT02519036IONIS-HTTRxIONIS-HTTRx*September 2017(3)
NCT02215616LEGATO-HDLaquinimod
NCT02197130AmaryllisPF-02545920
NCT02006472PRIDE-HDPridopidine
NCT03225833PRECISION-HD1WVE-120101February 2018(28)
NCT03225846PRECISION-HD2WVE-120102
NCT01795859FIRST-HDDeutetrabenazine
NCT02481674SIGNALVX15/2503August 2018(29)
NCT00712426CREST-ECreatine
NCT03761849GENERATION-HD1RG6042*January 2019(30)
NCT03344601PACE-HDPhysical activity
NCT02535884HD-DBSDeep brain stimulationJune 2019
NCT02453061TRIHEP3Triheptanoin

*IONIS-HTTRx and RG6042 refer to the same molecule.

In this edition, we highlight the HD-DBS trial (NCT02535884)(1), and the TRIHEP3 trial (NCT02453061)(2). We tabulate all currently registered and ongoing clinical trials in Tables 2 to 4. For further details on the methodology used, please refer to the first edition of Huntington’s Disease Clinical Trials Corner(3).

Table 2

Ongoing pharmacological clinical trials registered at the World Health Organization (WHO) International Clinical Trials Research Platform (ICTRP) for people with Huntington’s disease (HD)

Registration IDTrial nameInterventionMechanism of ActionPopulationComparisonMain outcomeStudy designEstimated EnrolmentSponsorLocation
NCT03854019*Dextromethorphan/quinidineMorphinan/class I antiarrhythmic agentHD with irritabilityPlaceboClinical efficacy at 6 and 13 weeksRandomized, double-blind, placebo-controlled, cross-over trial22University of Texas Health Science Center, Cures Within ReachUSA (single centre)
NCT03842969*GEN-EXTENDRG6042Allele- nonselective antisense oligonucleotideHDNoneSafety and tolerability at up to 5 yearsOpen-label extension950Hoffmann-La RocheUSA, Canada, Europe (multi centre)
NCT03761849GENERATION-HD1RG6042Allele- nonselective antisense oligonucleotideHDPlaceboClinical efficacy at 101 weeksRandomized, double-blind, placebo-controlled, parallel trial660Hoffmann-La RocheUSA, Canada, Europe (multi centre)
NCT03787758SAGE-718NMDA positive allosteric modulatorHDPlaceboSafety at 21 daysRandomized, double-blind, placebo-controlled, multiple ascending dose trial10Sage TherapeuticsN/S
NCT03575676SOM3355VMAT2 inhibitor and β1 antagonistEarly and moderate HD with choreaPlaceboChorea at 6 monthsRandomized, double-blind, placebo-controlled, cross-over trial30SOM Biotech SLSpain (multi centre)
NCT03515213FenofibratePPARα agonistHDPlaceboPharmacodynamics at 6 monthsRandomized, double-blind, placebo-controlled, parallel trial20University of California, IrvineUSA (single centre)
NCT03764215Tasigna HDNilotinibSelective Bcr-Abl tyrosine kinase inihbitorHDNoneSafety, tolerability and pharmacodynamics at 3 monthsOpen label, multiple ascending dose20Georgetown UniversityUSA (single centre)
NCT03342053IONIS-HTTRX OLEISIS 443139Allele- nonselective antisense oligonucleotideHDNoneSafety and tolerability at 74 weeksOpen label extension46Ionis Pharmaceuticals Inc.Canada, Germany and UK (multi-centre)
NCT03225833PRECISION-HD1WVE-120102Allele-selective antisense oligonucleotideHDPlaceboSafety and tolerability at 1 and 120 daysRandomized, double-blind, placebo-controlled, combined single ascending dose/multiple ascending dose trial48Wave Life Sciences Ltd.Canada and Poland (multi-centre)
NCT03225846PRECISION-HD2WVE-120102Allele-selective antisense oligonucleotideHDPlaceboSafety and tolerability at 1 and 120 daysRandomized, double-blind, placebo-controlled, combined single ascending dose/multiple ascending dose trial48Wave Life Sciences Ltd.Canada and Poland (multi-centre)
NCT02453061TRIHEP 3TriheptanoinAnaplerotic therapyHDSafflower oilPharmacodynamic efficacy at 6 monthsRandomized, double-blind, controlled, parallel trial100Institut National de la Santé Et de la Recherche Médicale, Ultragenyx Pharmaceutical IncFrance, Netherlands (multi centre)
NCT02509793TetrabenazineVMAT2 inhibitorHD with impulsivityNoneCognitive and behavioural effects at 8 weeksSingle group, open-label trial20University of Texas Health Science Center, and H. Lundbeck A/SUSA (single centre)
NCT02481674SIGNALVX15/2503Anti-semaphorin 4D monoclonal antibodyLate premanifest or early HDPlaceboSafety and tolerability at 15 and 21 monthsRandomized, double-blind, placebo-controlled, parallel trial240Vaccinex Inc., Huntington Study GroupUSA (multi centre)
NCT02336633REVHDResveratrolDietary supplementHDPlaceboNeuroimaging biomarkers at 1 yearRandomized, double-blind, placebo-controlled, parallel trial102Assistance Publique - Hôpitaux de ParisFrance (multi centre)
EUCTR2013-002545-10-SEOSU6162Open1309(-)-OSU616Monoaminergic stabilizerHD, PD, brain trauma, stroke, myalgic encephalomyelitis and narcolepsyNoneSafety at 3, 6 and 12 monthsSingle group, open-label trial240A. Carlsson Research ABSweden (multi centre)
NCT00514774UDCA-HDUrsodiolBile acidHDPlaceboSafety, tolerability and pharmacokinetics at 35 daysRandomized, double-blind, placebo-controlled, parallel trial21Oregon Health and Science University, Huntington Study Group, Huntington Society of CanadaN/S

N/S, not specified; PD, Parkinson’s disease; VMAT2, Vesicular Monoamine Transporter 2. Note: IONIS-HTTRx, ISIS 443139 and RG6042 refer to the same molecule. New trials since the last Clinical Trials Corner are indicated by*.

Table 3

Ongoing invasive non-pharmacological clinical trials registered at the World Health Organization (WHO) International Clinical Trials Research Platform (ICTRP) for people with Huntington’s disease (HD)

Registration IDTrial nameInterventionMechanism of ActionPopulationComparisonMain outcomeStudy designEsimated EnrolmentSponsorLocation
ISRCTN52651778TRIDENTFoetal stem cell transplantStem cell therapyEarly stage HDUsal careSafety at 4 weeksRandomized, open label, controlled, parallel trial30Cardiff UniversityUK (single centre)
NCT02728115SAVE-DHCellavitaStem cell therapyHDNoneSafety at 5 yearsNon-randomized, open label, uncontrolled, parallel trial6Azidus BrasilBrazil (single centre)
NCT03252535ADORE-HDCellavitaStem cell therapyHDPlaceboEfficacy at 120 daysRandomized, double-blind, placebo-controlled, parallel trial35Azidus BrasilBrazil (single centre)
NCT03297177Autologous stem/stromal cellsAutologous stem/stromal cell injectionHD, AD, PD, CBD, MSNoneSafety at 5 yearsSingle group, open-label trial300Healeon Medical Inc, Global Alliance for Regenerative Medicine, Regeneris MedicalUSA and Honduras (multi-centre)
NCT02535884HD-DBSGP DBSDeep brain stimulationModerate HD with choreaSham interventionEfficacy at 12 monthsRandomized, double-blind, sham-controlled, parallel trial50Heinrich-Heine University, KKS Netzwerk, Medtronic, The George Institute, EHDN, CHDI Foundation, Inc.Austria, France Germany, Switzerland (multi centre)
NCT01834053BMACHCBone Marrow Derived MNC transplantBone marrow transplantHD with choreaNoneCognitive and behavioural effects at 6 monthsSingle group, open-label trial50Chaitanya Hospital, PuneIndia (single centre)
NCT02263430GP DBSDeep brain stimulationHD with choreaSham stimulationEfficacy at 12 monthsRandomized, double-blind, placebo-controlled, parallel trial8Beijing Pins Medical Co., Ltd, Beijing Tiantan HospitalChina (single centre)
NCT02252380Magnetic Resonance Guided Focused UltrasoundExtracranial stereotactic radioablationHD, ET, HT, PD, WD, dystonia, TD, or orofacial dyskinesiasNoneAdverse events after the procedureSingle group, open-label trial10InSightecCanada (single centre)

AD, Alzheimer’s disease, CBD; Corticobasal Degeneration; DBS, deep brain stimulation; ET, Essential Tremor; GP, Globus pallidus; HT, Holmes Tremor; MNC, mononuclear cells; MS, Multiple Sclerosis; PD, Parkinson’s disease; TD, Tardive dyskinesia; WD, Wilson’s disease.

Table 4

Ongoing non-invasive non-pharmacological clinical trials registered at theWorld Health Organization (WHO) International Clinical Trials Research Platform (ICTRP) for people with Huntington’s disease (HD)

Registration IDTrial nameInterventionMechanism of ActionPopulationComparisonMain outcomeStudy designEsimated EnrolmentSponsorLocation
ACTRN126180 01717246Multidisciplinary therapy programExercise, cognitive training, lifestyle guidance and social activitiesPremanifestHDStandard of careFeasability and safetyClustered, non-randomized, open label, parallel trial40Edith Cowan University, Deakin University and LotterywestAustralia (two centres)
NCT03417583Neuropsychiatric treatment protocolMultidisciplinary interventionHD with neuropsychiatric symptomsStandard of careChange in quality of life at 18 monthsNon-randomized, assessor-blinded, parallel trial100Vanderbilt University Medical Center and Teva Pharmaceuticals USAUSA (single centre)
CTRI/2018/01/011359Repetitive transcranial magnetic stimulationTranscranial magnetic stimulationEarly to moderate HD and PDSham stimulationEfficacy at 5 daysRandomized, single-blind, placebo-controlled, parallel trial40Vinay GoyalIndia (single centre)
NCT03344601PACE-HDSupported structured aerobic exercise training programPhysiotherapyHDActivity as usualData completeness, recruitment, retention, safety, adherence, fidelity and acceptability at 12 monthsNested open-label, randomized controlled parallel trial120Cardiff University and CHDI Foundation, IncGermany, Spain and USA (multi centre)
ACTRN126170 01269325Swallowing skill trainingSpeech and language therapyHD and ALSNoneSwallowing function and quality of life at 2 weeksSingle group, open-label trial54University of CanterburyNew Zealand (single centre)
NCT02216474tDCSTranscranial magnetic stimulationHD or Tourette SyndromeSham stimulationEfficacy at 2 weeksRandomized, double-blind, placebo-controlled, cross-over trial100Birmingham and Solihull Mental Health NHS Foundation Trust, University of BirminghamUK (single centre)

AD, Alzheimer’s disease; ALS, Amyotrophic Lateral Sclerosis; ET, Essential Tremor; HT, Holmes Tremor; MS, Multiple Sclerosis; PD, Parkinson’s disease; TD, Tardive dyskinesia.

If you would like to draw attention to specific trials, please feel free to email us at: and .

In addition to the above, the published report of the IONIS-HTTRx trial (NCT02519036) is worthy of mention. The paper reports that monthly intrathecal IONIS-HTTRx/RG6042 – an antisense oligonucleotide that signals wild-type and mutant huntingtin pre-mRNA to be degraded by RNase H1 – was safe and well-tolerated, and produced dose-dependent reductions in cerebrospinal fluid mutant huntingtin in early HD patients (4). This is an interesting signal but caution should be exercised as to whether this reduction translates into a clinically significant benefit for people with HD. Further investigation into the effects of this drug are expected from the currently ongoing phase 3 GENERATION-HD1 trial (NCT03761849)(5) and associated studies(6– 10). These studies will help us better characterize the safety profile of this compound, define the most efficient posology, and understand if it is associated with a clinically relevant benefit, and towards which disease domain.

ONGOING CLINICAL TRIALS

A list of all ongoing clinical trials is given in Tables 24.

HD-DBS (NCT02535884)

Study title

Deep Brain Stimulation (DBS) of the Globus Pallidus (GP) in Huntington’s Disease (HD) (HD-DBS)(1).

Intervention

DBS of the GP (11) with Medtronic ACTIVA® PC neurostimulator (Model 37601).

Description

The HD-DBS trial, sponsored by Heinrich-Heine University, aims to evaluate the efficacy and safety of pallidal DBS in adults (18 or more years of age) with manifest HD (i.e. clinically symptomatic and genetically confirmed [CAG ≥36]) and moderate disease stage (defined by the investigators as an Unified Huntington’s Disease Rating Scale [UHDRS] total motor score [TMS] ≥30), chorea (UHDRS chorea score ≥10) and a Mattis Dementia Rating Scale ≥120, comparing with sham stimulation, for motor function.

People with juvenile or predominantly bradykinetic forms of the disease, postural instability, unstable medication in the 6 weeks previous to inclusion, unstable medical or psychiatric comorbidities, coagulopathies and/or increased risk of haemorrhage, implanted pacemaker or defibrillator, pregnant or breast-feeding are not eligible for this study.

This trial is an international, multi-centre, randomized, sham-controlled, double-blind, parallel study. It has 2 study arms: the stimulation group, where participants have stimulation turned on immediately after implantation of the stimulator; and the sham stimulation group, where participants will have a stimulator implanted but it will not be switched on. The study will last 12 weeks, and after that period all participants’ stimulators will be turned on.

The trial has already started recruitment, and has a recruitment target of 50 participants, over 4 countries (Austria, France, Germany and Switzerland) and 12 sites.

The primary outcome is the UHDRS TMS at 12 weeks, measured as the difference in the mean change from baseline between the stimulation arm and the sham-stimulation arm. The secondary outcomes include the UHDRS chorea score and the bradykinesia items, the Burke-Fahn-Marsden Dystonia Rating Scale, the Q-Motor choreomotography task, the Mattis Dementia Rating Scale, the Verbal Fluency Test, the Symbol Digits Modalities Test, the Stroop Test, the Hospital Anxiety and Depression Scales and the Snaith Irritability Scale, the Problem Behaviours Assessment Short Form, the Short Form 36 Health Survey, the Clinical Global Impression Scale, and safety.

Sponsors/funders

Heinrich-Heine University, KKS Netzwerk, Medtronic, the George Huntington Institute, EHDN and CHDI Foundation.

Comments

DBS is a relatively well-studied intervention for some manifestations of Parkinson’s disease, tremor and dystonia. DBS involves the surgical implantation of electrical electrodes in the deep brain structures, connected via a wire to an implantable pulse generator (i.e. stimulator) usually positioned subcutaneously in the pectoral region. Although the precise mechanisms of action are still not completely understood, this intervention is aimed at interrupting certain neuronal circuits.

In Parkinson’s disease DBS is frequently used to minimize levodopa-induced dyskinesia, which has a similar phenomenology to chorea in HD, but a different aetiology. This is accomplished by better controlling the cardinal features of PD, hence reducing the levodopa dose equivalents. There is still uncertainty about whether there is a direct effect of DBS over dyskinesia. In HD, chorea is thought to be caused by the loss of striatal projections to the indirect basal ganglia pathway and consequent thalamic overactivity (11), and although there is a shortage of good-quality evidence, some pilot studies have shown interesting preliminary results when manipulating these circuits with DBS in HD (12, 13).

The scarcity of data so far accumulated precludes drawing conclusions on the safety and efficacy profile of this intervention in HD, but it seems sensible to assume that this population may be susceptible to the same intervention-related adverse events as other tested populations. Disease-specific side effects may be more difficult to predict.

Only large well-controlled prospective controlled studies will allow us to fully understand the efficacy and safety profile of DBS in HD.

TRIHEP3 (NCT02453061)

Study title

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

Intervention

Triheptanoin oil 1 g/kg/day (14).

Description

The TRIHEP3 trial, sponsored by the Institut National de la Santé et de la Recherche Médicale and Ultragenyx Pharmaceutical Inc., aims to evaluate the effects of daily triheptanoin in adults (≥18 years of age) with genetically confirmed manifest HD (i.e. UHDRS TMS between 5 and 40), compared with daily safflower oil. People with a BMI <18 or >30, hypersensitivity to triheptanoin, major co-morbidities, history of severe head injury, pregnant or breast-feeding, or on tetrabenazine are not eligible.

TRIHEP3 is an international, multi-centre, randomized, double-blind, controlled, parallel phase 2 trial. It has 2 study arms: the active group, where participants receive triheptanoin oil 1 g/kg/day for 12 months; and the comparator group, where participants receive safflower oil 1 g/kg/day for 6 months and triheptanoin oil 1 g/kg/day for the following 6 months.

The study lasts 12 months, the first half over double-blinded conditions, and the second half as an open-label extension. Recruitment is currently closed and the study is being performed at one centre in France and one centre in the Netherlands. One hundred participants were recruited.

The primary outcomes are pharmacodynamics neuroimaging markers at 3 and 6 months - 31P-MRS and volumetric MRI. Secondary outcomes include the UHDRS, comprising the motor, functional and cognitive components, the Problem Behaviours Assessment Short Form, the Short Form 36 Health Survey, adverse events, tolerance and other neuroimaging biomarkers.

Sponsors/funders

Institut National de la Santé et de la Recherche Médicale and Ultragenyx Pharmaceutical Inc.

Comments

Albeit with a low success rate (15), several dietary nutrients with possible effects over metabolic processes have been tested in HD over the years, including d-α-tocopherol (16), idebenone (17), co-enzyme Q10 (18), ethyl-eicosapentaenoate (19– 21), and creatine (22– 24).

Triheptanoin is an odd-chain triglyceride with anaplerotic properties (i.e. it replenishes biochemical cycles with intermediate metabolites), providing the Krebs cycle with both acetyl-CoA and propionyl-CoA. So far, triheptanoin has been tested for several disorders of the brain metabolism, including pyruvate decarboxylase deficiency, and GLUT1 deficiency where a significant symptomatic effect was demonstrated in a small open-labelstudy (25).

In HD, several lines of evidence support the existence of a dysfunction of the energy metabolism, including the Krebs cycle, oxidative phosphorylation and glycolysis. Two small open-label studies in HD showed that triheptanoin may have the potential to bring peripheral (26) and central nervous system metabolic biomarkers (27) to levels observed in healthy controls. They also anticipate triheptanoin to be well tolerated (26, 27), and overall the cumulative evidence suggests a good safety profile for doses between 1 to2.5 g/kg/day(14).

The TRIHEP3 trial will be completed by the end of 2019 and the results are expected in mid-2020.

CONFLICTS OF INTEREST

FBR and EJW were sub-investigators on LEGATO-HD (NCT02215616), IONIS HTTRx (NCT02519036) and IONIS HTTRx OLE (NCT03342053), and are sub-investigators on the Roche GENERATION-HD (NCT03761849), Roche Natural History Study (NCT03664804) and Roche GEN-EXTEND (NCT03842969) trials, and EJW was a sub-investigator on the Amaryllis (NCT02197130). EJW is the chief investigator of the Roche GEN-PEAK trial (NCT04000594) and FBR is a sub-investigator. JJF was principal investigator on LEGATO-HD and on a trial of ethyl-eicosapentanoate in Huntington’s disease. The authors did not make use of confidential or privileged information: all materials included in this manuscript were collected from publicly available sources. FBR has provided consultancy services to GLG. EJW has participated in scientific advisory boards with Hoffmann-La Roche Ltd, Ionis, Shire, GSK, Wave Life Sciences, PTC Therapeutics, Takeda and Mitoconix. All honoraria were paid through UCL Consultants Ltd, a wholly owned subsidiary of UCL. Their Host Institution, University College London Hospitals NHS Foundation Trust, has received funds as compensation for conducting clinical trials for Ionis Pharmaceuticals, Pfizer and Teva Pharmaceuticals. Hoffman La Roche Ltd has supported UCL with research funding for EJW. In view of the support to both regular authors from Hoffman-La Roche Ltd, JJF was invited to be a co-author to ensure the sections on the Ionis/Roche program were suitably balanced.

JJF received grants from GlaxoSmithKline, Grunenthal, Fundação MSD (Portugal), TEVA, MSD, Allergan, Novartis, Medtronic. He received consultancy fees from GlaxoSmithKline, Novartis, TEVA, Lundbeck, Solvay, BIAL, Merck-Serono, Merz, Ipsen, Biogen, Acadia, Allergan, Abbvie, Sunovion Pharmaceuticals. He is employed by Faculdade de Medicina de Lisboa and CNS - Campus Neurológico Sénior. He also participated in advisory boards for Bial and expert testimony to Novartis.

ACKNOWLEDGMENTS

The authors are supported by CHDI Foundation, Inc. (salary support to FBR and EJW).

REFERENCES

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Heinrich-Heine University, KKS Netzwerk, Medtronic, The George Huntington Institute, EHDN, CHDI Foundation Inc. Deep Brain Stimulation (DBS) of the Globus Pallidus (GP) in Huntington’s Disease (HD). https://ClinicalTrials.gov/show/NCT02535884; 2014.

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Institut National de la Santé Et de la Recherche Médicale, Ultragenyx Pharmaceutical Inc. A Comparative Phase 2 Study Assessing the Efficacy of Triheptanoin, an Anaplerotic Therapy in Huntington’s Disease. https://ClinicalTrials.gov/show/NCT02453061; 2015.

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Tabrizi SJ , Leavitt BR , Landwehrmeyer GB , Wild EJ , Saft C , Barker RA , et al. Targeting huntingtin expression in patients with huntington’s disease. The New England Journal of Medicine. 2019.

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Hoffmann-La Roche. A Study to Evaluate the Efficacy and Safety of Intrathecally Administered RO7234292 (RG6042) in Patients With Manifest Huntington’s Disease. https://ClinicalTrials.gov/show/NCT03761849; 2018.

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Ionis Pharmaceuticals I. Study in Huntington’s Disease Patients Who Participated in Prior Investigational Studies of ISIS 443139. https://ClinicalTrials.gov/show/NCT03342053; 2017.

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Hoffmann-La Roche. Study to Measure Cerebrospinal Fluid Mutant Huntingtin Protein in Participants With Early Manifest Stage I or Stage II Huntington’s Disease. https://ClinicalTrials.gov/show/NCT03664804; 2018.

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Hoffmann-La Roche. An Open-Label Extension Study to Evaluate Long-Term Safety and Tolerability of RO7234292 (RG6042) in Huntington’s Disease Patients Who Participated in Prior Roche and Genentech Sponsored Studies. https://ClinicalTrials.gov/show/NCT03842969; 2019.

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Puri BK , Leavitt BR , Hayden MR , Ross CA , Rosenblatt A , Greenamyre JT , et al. Ethyl-EPA in Huntington disease: A double-blind, randomized, placebo-controlled trial. Neurology. 2005;65(2):286–92.

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Huntington Study Group T-HDI, Dorsey ER , Shoulson I , Leavitt B , Ross C , Beck CA , et al. Randomized controlled trial of ethyl-eicosapentaenoic acid in Huntington disease: The TREND-HD study. Archives of Neurology. 2008;65(12):1582–9.

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Ferreira JJ , Rosser A , Craufurd D , Squitieri F , Mallard N , Landwehrmeyer B . Ethyl-eicosapentaenoic acid treatment in Huntington’s disease: A placebo-controlled clinical trial. Movement Disorders: Official Journal of the Movement Disorder Society. 2015;30(10):1426–9.

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Rosas HD , Doros G , Gevorkian S , Malarick K , Reuter M , Coutu JP , et al. PRECREST: A phase II prevention and biomarker trial of creatine in at-risk Huntington disease. Neurology. 2014;82(10):850–7.

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Hersch SM , Schifitto G , Oakes D , Bredlau A-L , Meyers CM , Nahin R , et al. The CREST-E study of creatine for Huntington disease: A randomized controlled trial. Neurology. 2017;89(6):594–601.

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Mochel F , Hainque E , Gras D , Adanyeguh IM , Caillet S , Heron B , et al. Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1 deficiency. J Neurol Neurosurg Psychiatry. 2016;87(5):550–3.

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Mochel F , Duteil S , Marelli C , Jauffret C , Barles A , Holm J , et al. Dietary anaplerotic therapy improves peripheral tissue energy metabolism in patients with Huntington’s disease. European Journal of Human Genetics: EJHG. 2010;18(9):1057–60.

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Adanyeguh IM , Rinaldi D , Henry PG , Caillet S , Valabregue R , Durr A , et al. Triheptanoin improves brain energy metabolism in patients with Huntington disease. Neurology. 2015;84(5):490–5.

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