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Huntington’s Disease Clinical Trials Corner: August 2018


In the third edition of the Huntington’s Disease Clinical Trials Corner we list all currently registered and ongoing clinical trials, expand on the SIGNAL trial (NCT02481674), and cover the recently finished CREST-E trial (NCT00712426).


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

Registration IDTrial nameInterventionEdition
NCT02519036IONIS-HTTRxIONIS-HTTRxSeptember 2017 [4]
NCT03225833PRECISION-HD1WVE-120101February 2018 [15]
NCT02481674SIGNALVX15/2503August 2018

In this edition, we highlight the SIGNAL trial (NCT02481674) [1], and summarise the results of the recently published CREST-E trial (NCT00712426) [2, 3]. Finally 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 September 2017 edition of Huntington’s Disease Clinical Trials Corner [4].

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 ofPopulationComparisonMain outcomeStudy designEstimatedSponsorLocation
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 therapyHDPlaceboPharmacodynamic efficacy at 6 monthsRandomized, double-blind, placebo-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)
NCT02507284STAIRSRX246Vasopressin 1a Receptor AntagonistEarly and moderate HD with irritabilityPlaceboFeasibility at 12 weeksRandomized, double-blind, placebo-controlled, parallel trials108Azevan Pharmaceuticals, National Institute of Neurological Disorders and Stroke (NINDS), and NeuroNEXT NetworkUSA (multi 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)
NCT02215616LEGATO-HDLaquinimodImmunomodulatory moleculeHDPlaceboEfficacy at 1, 3, 6, and 12 monthsRandomized, double-blind, placebo-controlled, parallel trial400Teva Branded Pharmaceutical Products, R&D Inc.Canada, Czech Republic, France, Germany, India, Israel, Italy, Netherlands, Portugal, Russia, Spain, UK, USA (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)
NCT00652457MEM-HDMemantineNMDA receptor antagonistHD and memory or concentration difficultiesPlaceboEfficacy at 3 and 6 monthsRandomized, double-blind, placebo-controlled, cross-over trial60University of California, San Diego, Forest LaboratoriesUSA (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
ACTRN12616001611415VCAS-HDVareniclineNicotinic acid receptor partial agonistHDPlaceboEfficacy at 10 weeksRandomized, double-blind, placebo-controlled, parallel trial40University of AucklandNew Zealand (single centre)

N/S, not specified; PD, Parkinson’s disease; VMAT2, Vesicular Monoamine Transporter 2. 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
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, 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. New trials since the last Clinical Trials Corner are indicated by *.

Table 4

Ongoing non-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
CTRI/2018/01/011359*Repetitive 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, asfety, adherence, fidelity and acceptability at 12 monthsNested open-label,randomized controlled parallell trial120Cardiff University and CHDI Foundation, IncGermany, Spain and USA (multi centre)
NCT03306888Physical Activity Coaching InterventionPhysiotherapyPremanifest and early HDNoneChange in physical activity at 4 monthsSingle group, open-label trial14Columbia UniversityUSA (single centre)
ACTRN12617001269325Swallowing skill trainingSpeech and language therapyHD and ALSNoneSwallowing function and quality of life at 2 weeksSingle group, open-label trial54University of CanterburyNew Zealand (single centre)
NCT02990676CogTrainHDComputerised Cognitive TrainingCognitive trainingHDNo interventionFeasibility at 4 yearsOpen-label, controlled, parallel trial50Cardiff UniversityUK (single centre)
NCT02464293Mindfulness-based Cognitive TherapyCognitive therapyPremanifest and early HD with behavioural symptomsNoneBehavioural effect at 2 weeks, 3 months and 1 yearSingle group, open-label trial16Lancaster University, Central Manchester University Hospitals NHS Foundation TrustUK (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)
NCT02750982Laughter TherapyCognitive therapyHD, AD, ALS, brain injury, MS, PD, post/stroke or spinal cord injuryNoneBehavioural effects at 8 weeksSingle group, open-label trial24Brown, Theodore R., M.D., MPHUSA (single centre)
NCT01602276tDCSTranscranial magnetic stimulationSubcortical brain damage, including HDSham stimulationEfficacy at 1 monthRandomized, single-blind, placebo-controlled, cross-over trial, with parallel healthy control arm150Johns Hopkins UniversityUSA (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. New trials since the last Clinical Trials Corner are indicated by *.

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


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

SIGNAL (NCT02481674)

Study title

VX15/2503 Treatment for Huntington’s Disease (SIGNAL) [1].


VX15/2503 (20 mg/kg), an anti-semaphorin 4D antibody [5].


The SIGNAL trial, sponsored by Vaccinex (Rochester, NY, USA), aims to evaluate the safety, tolerability, pharmacokinetics and efficacy of monthly intra-venous VX15/2503 in adults (≥21 years of age) with late prodromal (i.e. a CAG-age Product superior to 200 and a Unified Huntington’s Disease Rating Scale [UHDRS] Diagnostic Confidence Level of 2 or 3) and early manifest HD (i.e. a UHDRS Diagnostic Confidence Level of 4 and a UHDRS Total Functional Capacity [TFC] above or equal to 11), comparing with intra-venous placebo, for disease modification.

This trial is phase 2, multi-centre, national, randomized, placebo controlled, double-blind, parallel study. It is divided into cohort A and cohort B, and will involve 240 participants. Cohort A recruited 36 participants and was completed in December 2015. In this cohort participants received VX15/2503 or placebo for 6 months, and VX15/2503 for another 6 months in an open label extension, followed by a 3-month period of follow up. Enrolment in cohort B is completed. This cohort is underway and 53 participants will receive VX15/2503 or placebo for 36 months, followed by 3 or 6 months of follow up. The remainder of Cohort B’s participants will receive VX15/2503 or placebo for 18 months, followed by 6 months of follow up. The exact numbers and durations have not been confirmed publicly, to our knowledge. The trial has a recruitment target of 240 participants; recruitment is currently open at various sites in the United States of America and Canada.

VX15/2503 is humanized IgG4 monoclonal antibody against semaphorin 4D. Each participant’s involvement will last for at least 15 months and up to a maximum of 42 months.

The primary outcome is safety and tolerability. Secondary outcomes involve brain imaging with MRI, FDG-PET, 11C-PBR28 PET; clinical features; pharmacokinetics and pharmacodynamics. Exploratory analysis include cerebrospinal fluid biomarkers.


Vaccinex Inc., and the Huntington Study Group.


Semaphorins are a family of proteins whose name derives from semaphore (from the Greek for sign-bearer). Initially described as signalling proteins for neuronal growth and regeneration, today they are known to be involved in many other processes such as the immune response. Semaphorin 4D, or CD100, is an axon-guiding molecule, and a B and T cell modulator.

In a YAC128 transgenic Huntington’s disease mouse model, targeting semaphorin 4D with monoclonal antibodies seemed to ameliorate striatal cortical and corpus callosum atrophy, and behavioural phenotype [6]. However, as of today, there is no published evidence supporting that the semaphorin family may be a therapeutic target in humans with HD.

Previous clinical trials involving 42 patients with advanced solid tumours (4 weekly doses up to 20 mg/kg per week) [7] and 50 patients with multiple sclerosis (single ascending dose up to 20 mg/kg) [8] showed VX15/2503 to be relatively well tolerated and safe, but were neither designed nor powered to assess clinical benefit.

Preliminary data from SIGNAL’s Cohort A have been presented at public meetings by Vaccinex, reporting interesting neuroimaging and neurometabolic results (PET imaging) in the VX15/2503 arm. Previous reports of atrophy slowing in HD have not ultimately been associated with clinical benefit or slowing of clinical progression [9–11], so such reports need to be treated with caution and interpreted in their full context.


CREST-E (NCT00712426)

Study title

Creatine Safety, Tolerability, & Efficacy in Huntington’s Disease [2, 3].


Creatine monohydrate, a nutritional supplement.


The goal of CREST-E trial was to assess the effects of up to 40 gm of oral creatine monohydrate daily compared with oral placebo on functional decline in adults with early manifest HD (i.e. motor signs characteristic of HD plus a positive family history for HD or a HTT CAG repeat length ≥ 36 plus a UHDRS Total Functional Capacity ≥ 7).

This trial was a phase 3, multi-centre, international, randomized, placebo-controlled, double-blind, parallel study. Although designed to recruit 650 participants from Australia, Canada, New Zealand, and the United States, the trial only recruited 553 participants before being halted for futility after an interim analysis. Participant involvement lasted for up to 48 months.

The primary outcome was rate of change from baseline in the UHDRS TFC at weeks 12 to 48 depending on each participant’s date of enrolment. The secondary outcomes included changes in other UHDRS scores, adverse events, tolerability, quality of life, and several biofluid and imaging biomarkers.


Massachusetts General Hospital, University of Rochester, National Center for Complementary and Integrative Health.


The trial was completed on December 2014 and the results published in July 2017 [2]. CREST-E was the largest clinical trial undertaken in HD. The results showed that although no major safety concerns were noted apart from an increased risk of diarrhoea. Creatine did not have an effect on functional decline in HD, nor on any other outcome studied.

Creatine has previously been studied in pre-symptomatic and symptomatic individuals. In PRECREST (NCT00592995) [9, 12] 64 premanifest and at-risk individuals were enrolled in a 6-month randomized placebo-controlled double-blinded study of up to 15 gm of oral creatine monohydrate bid, followed by a 12-months open-label extension period. In CREST-HD (NCT00026988) [13, 14] 69 people with manifest HD were enrolled in a 16-week randomized placebo-controlled double-blinded study of 4 gm of oral creatine monohydrate bid.

As in CREST-E, no safety concerns emerged in PRECREST apart from increased risk of nausea and diarrhoea, but there was no change in clinical measures.

Further creatine clinical trials have been registered and the recruitment is completed (Pre-CREST-X [NCT01411150], Pre-CREST-X2 [NCT01411163], CREST-X [NCT01412151]) but to our knowledge, their results are not public yet.


FBR and EJW were sub-investigators on LEGATO-HD (NCT02215616), and are sub-investigators on the IONIS HTTRx (NCT02519036) and IONIS HTTRx OLE (NCT03342053) trials, and EJW was a sub-investigator on the Amaryllis study (NCT02197130). The authors did not make use of confidential or privileged information: all materials included in this manuscript were collected from publicly available sources. EJW has participated in scientific advisory boards with Hoffmann-La Roche Ltd, Ionis, Shire, GSK, Wave Life Sciences, PTC Therapeutics 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.


The authors are supported by CHDI Foundation, Inc. (salary support to FBR for conduct of the HDClarity study) and Medical Research Council UK (salary support to EJW).



Vaccinex Inc. Huntington Study Group. VX15/2503 Treatment for Huntington's Disease, 2015.


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.


Massachusetts General Hospital. Creatine Safety. Tolerabil-ity, & Efficacy in Huntington's Disease (CREST-E), 2008.


Rodrigues FB , Wild EJ Clinical Trials Corner: September 2017. J Huntingtons Dis 2017;6(3):255–63.


Leonard JE , Fisher TL , Winter LA , Cornelius CA , Reilly C , Smith ES , et al. Nonclinical Safety Evaluation of VX15/a Humanized IgG4 Anti-SEMA4D Antibody. Molecular cancer therapeutics 2015;14(4):964–72.


Southwell AL , Franciosi S , Villanueva EB , Xie Y , Winter LA , Veeraraghavan J , et al. Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease. Neurobiology of Disease 2015;76, 46–56.


Patnaik A , Weiss GJ , Leonard JE , Rasco DW , Sachdev JC , Fisher TL , et al. Safety, pharmacokinetics, and pharmacodynamics of a humanized anti-semaphorin 4D antibody, in a first-in-human study of patients with advanced solid tumors. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2016;22(4):827–36.


LaGanke C , Samkoff L , Edwards K , Jung Henson L , Repovic P , Lynch S , et al. Safety/tolerability of the anti-semaphorin 4D Antibody VX15/in a randomized phase 1 trial. Neurology® Neuroimmunology & Neuroinflammation. 2017;4(4):e367.


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.


Puri BK , Bydder GM , Counsell SJ , Corridan BJ , Richardson AJ , Hajnal JV , et al. MRI and neuropsychological improvement in Huntington disease following ethyl-EPA treatment. NeuroReport 2002;13(1):123–6.


Puri BK , Bydder GM , Manku MS , Clarke A , Waldman AD , Beckmann CF Reduction in cerebral atrophy associated with ethyl-eicosapentaenoic acid treatment in patients with Huntington’s disease. The Journal of International Medical Research 2008;36(5):896–905.


Massachusetts General Hospital Creatine Safety and Tolerability in Premanifest HD: PRECREST 2008. .


Hersch SM , Gevorkian S , Marder K , Moskowitz C , Feigin A , Cox M , et al. Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2’dG. Neurology 2006;66(2):250–2.


National Center for Complementary and Integrative Health. Creatine Therapy for Huntington’s Disease, 2001.


Rodrigues FB , Wild EJ Huntingtons Disease Clinical Trials Corner: February Journal of Huntington’s Disease 2018;7(1):89–98.