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Huntington’s Disease Clinical Trials Corner: January 2019

Abstract

In this edition of the Huntington’s Disease Clinical Trials Corner we expand on the GENERATION-HD1 and PACE-HD 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(33)
NCT03225846PRECISION-HD2WVE-120102
NCT01795859FIRST-HDDeutetrabenazine
NCT02481674SIGNALVX15/2503August 2018(34)
NCT00712426CREST-ECreatine
NCT03761849GENERATION-HD1RG6042*January 2018
NCT03344601PACE-HDPhysical activity

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

In this edition, we highlight the GENERATION-HD1 trial (NCT03761849) [1], and the PACE-HD trial (NCT03344601) [2], and briefly summarise the trial evidence around physiotherapy and exercise interventions in HD. 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 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
NCT03761849*GENERATION-HD1RG6042Allele-nonselective antisense oligonucleotideHDPlaceboClinical efficacy at 101 weeksRandomized, double-blind, placebo-controlled, parallel trial660Hoffmann-La RocheUSA, Canada, Europe (multi centre)
NCT03787758*SAGE-718NMDA positive allosteric modulatorHDPlaceboSafety at 21 daysRandomized, double-blind, placebo-controlled, multiple ascending dose trial10Sage TherapeuticsN/S
NCT03575676*SOM3355VMAT2 inhibitor and β1 antagonistEarly and moderate HD with choreaPlaceboChorea at 6 monthsRandomized, double-blind, placebo-controlled, cross-over trial30SOM Biotech SLSpain (multi centre)
NCT03515213*FenofibratePPARα agonistHDPlaceboPharmacodynamics at 6 monthsRandomized, double-blind, placebo-controlled, parallel trial20University of California, IrvineUSA (single centre)
NCT03764215*Tasigna 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 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)
EUCTR2013-002545-10-SEOSU6162 Open1309(–)-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
ACTRN126- 16001611415VCAS-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. 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
ISRCTN52651778*TRIDENTFoetal stem cell transplantStem cell therapyEarly stage HDUsal careSafety at 4 weeksRandomized, open label, controlled, parallel trial30Cardiff UniversityUK (single centre)
NCT02728115*SAVE-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, 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
ACTRN1261800 1717246*Multidisciplinary 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)
NCT03417583*Neuropsychiatric 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)
NCT03306888Physical Activity Coaching InterventionPhysiotherapyPremanifest and early HDNoneChange in physical activity at 4 monthsSingle group, open-label trial14Columbia UniversityUSA (single centre)
ACTRN1261700 1269325Swallowing 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)

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 .

In addition to the above, the published report of the PRIDE-HD trial (NCT02006472) is worthy of mention. The paper reports that “the study did not meet its primary of secondary endpoints at 26 weeks” [4], confirming the results of previous trials [5–7] and suggests that pridopidine is unlikely have an effect on the motor symptoms of HD as assessed with the Unified Huntington’s Disease Rating Scale (UHDRS) Total Motor Score (TMS).

ONGOING CLINICAL TRIALS

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

GENERATION-HD1 (NCT03761849)

Study title

A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Phase III Clinical Study to Evaluate the Efficacy and Safety of Intrathecally Administered RO7234292 (RG6042) in Patients With Manifest Huntington’s Disease [1].

Intervention

RG6042 (120 mg) – formerly known as IONIS-HTTRx / ISIS443139 – an antisense oligonucleotide that targets the HTT transcript allele-nonspecifically with the aim of lowering the production of mutant huntingtin protein [8].

Description

The GENERATION-HD1 trial, sponsored by Hoffmann-La Roche, aims to evaluate the efficacy, safety, and biomarker effects of monthly and bimonthly (i.e. every other month) 120 mg of intrathecal RG6042 in adults (25 to 65 years of age) with manifest HD (i.e. a UHDRS Diagnostic Confidence Level of 4, a UHDRS Independence Score [IS] above or equal to 70, and a CAG-age Product equal or greater than 400) and intact functional independence at baseline to maintain self-care and core activities of daily living, comparing with intrathecal placebo, for disease modification.

This trial is a phase 3, international, multi-centre, randomized, placebo controlled, double-blind, parallel study. It will have 3 study arms: monthly intrathecal injections of 120 mg RG6042; monthly intrathecal injections alternating between 120 mg RG6042 and placebo; and monthly intrathecal placebo. The intervention will be administered for 25 months, and participants will be followed for 29 months. All participants are expected to be invited to an optional open-label extension (OLE) involving monthly or bimonthly (i.e. every other month) drug administration after the end of the blinded phase of the study, assuming the program is continuing.

The trial had not started recruitment at the time of writing, but has a recruitment target of 660 participants, over around 15 countries and 80 to 90 study sites, and it is planned to start enrolment by early 2019. It is currently public that recruitment will happen in the United States of America and Canada, where expected clinical sites were announced in December [9]. Details about further countries and sites will be released in the future.

This pivotal trial will have two primary clinical outcomes for regulatory purposes, the UHDRS Total Functional Capacity (TFC) for the FDA, and the composite UHDRS (cUHDRS) [10] for the EMA [11]. Secondary outcomes will involve other components of the UHDRS, clinical global impression, adverse events, the Montreal Cognitive Assessment (MoCA), the Columbia-Suicide Severity Rating Scale (C-SSRS), pharmacokinetic markers, cerebrospinal fluid mutant huntingtin and neurofilament light chain, and MRI brain volumes.

Sponsors/funders: Hoffmann-La Roche

Comments

This trial is the first to test huntingtin-lowering in a pivotal phase 3 trial, and is part of a development plan that includes the completed first-in-man phase 1b/2a IONIS-HTTRX (NCT02519036) trial [12], its ongoing OLE (NCT03342053) [13], the now-recruiting HD Natural History Study (NCT03664804) [14], and the imminent GENERATION-HD1 (NCT03761849) trial [1]. The phase 1b/2a involved 46 people with early stage HD and showed RG6042 to be safe and well-tolerated, and to reduce cerebrospinal fluid mutant huntingtin concentrations in a dose-dependent manner [15]. Results are currently being prepared for peer-reviewed publication [11]. After completion, all participants were invited to an OLE study aimed at studying long-term safety, tolerability, pharmacokinetics and pharmacodynamics of RG6042 over 15 months; this is currently ongoing. Participants entering the OLE were randomly allocated to monthly or bimonthly intrathecal doses of 120 mg RG6042.

Table 5

Minimum age at which individuals with each HTT CAG count will have a CAP score of ≥400, permitting them to meet this inclusion criterion for Generation-HD1 and related trials

CAGMinimum age
36Ineligible
37Ineligible
38Ineligible
39Ineligible
4063.09
4154.50
4247.96
4342.83
4438.68
4535.27
4632.41
4729.99
4827.89
4926.08
50 or over25

Note that those with CAG counts of 36–39 will never meet this criterion while they still meet the maximum age inclusion criterion of 65, while those with repeats of 50 or over all meet the CAP score cutoff, but would need to additionally meet the minimum age inclusion criterion of 25.

The HD Natural History Study is a prospective longitudinal observational study that aims to recruit 100 people with early stage HD, matched individually to the participants of the open label extension study [16]. It aims to measure clinical and biomarkers (i.e. cerebrospinal fluid neurofilament light chain, mutant huntingtin and tau, brain MRI volumes, and digital biomarkers) over a 15-month period in a sample comparable to the phase 1b/2a and open label extension studies. Participants are being recruited in United States of America, Canada, Germany and United Kingdom. Participants will be offered continued open-label access to RG6042 after study termination.

Notably, for the pivotal phase 3 trial, GENERATION-HD1, Roche has opted for an enrichment strategy based on the inclusion criterion “CAG-age Product superior to 400”. The CAG-age product (CAP score) is an estimate of lifetime exposure to mHTT toxicity [17], given by:

[HTT CAG repeat length – 33.66] × age

Together with the remaining inclusion criteria, namely the UHDRS Diagnostic Confidence Level of 4, a UHDRS IS above or equal to 70, and functional independence at baseline, the use of a CAP score cutoff aims to produce a relatively homogeneous sample of early stage participants, whose expected progression during trial follow-up is greater and less variable [17]. This should improve the statistical power of the sample. It produces rigid minimum age cutoffs for each HTT CAG repeat length, as shown in Table 5. This criterion will doubtless be a point of focus in discussions with potential volunteers.

PACE-HD (NCT03344601)

Study title

A Longitudinal Cohort Study With Nested Randomised Pragmatic Controlled Trial to Evaluate Physical Activity and Exercise Related Outcomes in People With Huntington’s Disease (PACE-HD) [2].

Intervention

Supported structured aerobic exercise training program (18 face-to-face coaching sessions of ∼1 hour).

Description

The PACE-HD trial, sponsored by Cardiff University and CHDI Foundation, Inc., aims to evaluate the feasibility, tolerability, and safety of supported structured aerobic exercise training program in adults (≥18 years of age) with genetically confirmed early manifest HD, compared with activity as usual.

PACE-HD is an international, multi-centre, observation study with a nested randomized, controlled, open label, parallel study. It will involve 120 participants, 60 of whom will take part on a longitudinal observational evaluation of physical fitness and physical activity over a period of 12 months, while the remaining 60 will be randomized to a supported structured aerobic exercise training program, or exercise as usual over a period of 12 months. Recruitment is currently open at various sites in the United States of America, Germany, and Spain.

The primary outcomes are data completeness, recruitment, retention, safety, adherence, fidelity, and acceptability. Secondary outcomes include exercise tests, walk endurance measures, the HD Pro-Triad, the Brunel Lifestyle Physical Activity Questionnaire, and digital biomarkers.

Sponsors/funders: Cardiff University and CHDI Foundation, Inc.

Comments

With multiple trials of agents intended to engage with the core pathobiology of HD underway, and more planned, the relevance of clinical interventions such as rehabilitation therapies, as both stand-alone and adjunctive therapies, has never been more significant. Similar to current management guidelines for Parkinson’s disease [18] and multiple sclerosis [19], rehabilitation therapies - including physiotherapy, occupation therapy, exercise and physical activity - could be used alongside disease-modifying interventions with the potential to maximize patient outcomes.

Animal models of HD have provided pre-clinical evidence that exercise has the potential to modify disease progression. In R6/1 mice, sustained wheel running was shown to improve gait and motor coordination, as well as reduce striatal neuron loss [20]. More recent work with the longer life-span CAG140 mouse model demonstrated that 6 months of treadmill training resulted in increased striatal dopamine D2 receptor expression and dopamine neurotransmitter levels, reduction in HTT aggregate formation, as well as improved behavioural and cognitive symptoms [21]. These pre-clinical findings have set the stage for several clinical feasibility studies in people with early and moderate HD [22–25], as well as in several multi-disciplinary rehabilitation trials [26–30].

Combined pre-clinical and clinical data provide support for the evaluation of exercise as a therapeutic intervention strategy in HD. A recent systematic review reported on findings from 20 studies and found preliminary support for the benefits of exercise and physical activity in terms of motor function, gait speed, and balance [31, 32]. The review also reported a range of physical and social benefits identified through patient-reported outcomes. Interventions incorporating aerobic and strengthening exercises were most prevalent across studies, and several studies noted improvement or maintenance of motor function over 9 months or longer.

In order for rehabilitation interventions to be considered an important adjunctive therapy alongside pharmacological interventions, high-quality studies using innovative statistical methods and trials designs are needed. PACE-HD is a pragmatic study that includes both a longitudinal observational study and a nested (i.e. within-cohort) randomized controlled trial of a 12-month physical therapy and exercise intervention. The intervention incorporates the use of wearable physical activity monitors to measure both outcomes and activity levels throughout the trial. The study is conducted alongside Enroll-HD, which minimizes subject burden and will provide a basis for comparative analysis on disease progression measures. Results of this study are due in the summer of 2020.

A formal Clinical Guideline for Exercise in HD is currently in development. This will provide evidence-based recommendations for healthcare providers and persons with HD, and is planned to be available later in 2019.

CONFLICTS OF INTEREST

FBR and EJW were sub-investigators on LEGATO-HD (NCT02215616) and IONIS HTTRx (NCT02519036), and are sub-investigators on the IONIS HTTRx OLE (NCT03342053) and Roche Natural History Study (NCT03664804) 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. Hoffman La Roche Ltd has supported UCL with research funding for EJW. LQ received honoraria from the Huntington Study Group and royalties from Elsevier Publishing.

ACKNOWLEDGMENTS

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

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