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Clinical Trials Corner: September 2017

Abstract

Clinical Trials Corner of Journal of Huntington’s Disease will regularly review ongoing and recently completed clinical trials in Huntington’s disease. In this inaugural issue, we list all currently registered and ongoing clinical trials, expand on LEGATO-HD and IONIS-HTTRx, and cover two recently finished trials: Amaryllis and Pride-HD.

INTRODUCTION

Clinical Trials Corner of Journal of Huntingtons Disease is a new, regular, peer-reviewed section devoted to highlighting ongoing or recently completed clinical trials in Huntington’s disease (HD).

To do so, we will gather and curate data from the World Health Organization (WHO) International Clinical Trials Search Portal (ICTRP)— a central database that contains the trial registration datasets provided by 17 clinical trial registries [1], including the EU Clinical Trials Register (EU-CTR), the USA ClinicalTrials.gov, among others— using the keywords “Huntingtons” and “Huntington”. As trial registration has been settled as a condition for publication by the International Committee of Medical Journal Editors (ICMJE) since 2005 [2], and the following year the WHO supported this measure, this strategy is expected to harvest the majority of ongoing clinical trials [3]. We will use only publicly available information to describe the trials and theirresults.

There are only two drugs specifically approved for HD [4]: tetrabenazine [5] and deutetrabenazine [6], both with a moderate effect on involuntary movements. No intervention has shown to modify disease progression so far [7]. That being said, almost one hundred clinical trials and 50 different interventions have been or are currently being tested in HD [8]. It is clear that modifying the progression of HD is exceptionally difficult; that success in preclinical models so far has failed to anticipate the outcome of subsequent human trials; and that there is a need for not only better drugs, but better means of deciding which drugs we should test in patients.

In this inaugural Clinical Trials Corner, we will list all currently registered and ongoing clinical trials, expand on LEGATO-HD (NCT02215616) and IONIS-HTTRx (NCT02519036), and cover two recently finished trials: Amaryllis (NCT02197130) and Pride-HD (NCT02006472). For future editions, we will summarize current efforts and recent developments as well as providing in-depth information on notable trials.

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

ONGOING CLINICAL TRIALS

A list of ongoing clinical trials is given in Tables 12 and 3.

Table 1

Ongoing pharmacological clinical trials registered at the World Health Organization (WHO) International Clinical Trials Research Platform (ICTRP) for people with Huntington’s disease (HD). NINDS, National Institute of Neurological Disorders and Stroke; HSG, Huntington Study Group; N/S, not specified; PD, Parkinson’s disease; VMAT2, Vesicular Monoamine Transporter 2

Registration IDTrial nameInterventionMechanism ofPopulationComparisonMain outcomeStudy designEstimatedSponsorLocation
ActionEnrolment
EUCTR2016-003730-25-NLCHALLENGE-HDSBT-020Mitochondria-targeted cytoprotective peptideEarly HDPlaceboSafety and tolerability at 7 and 28 daysRandomized, double-blind, placebo-controlled, parallel trial24Stealth BiotherapeuticsNetherlands (single center)
NCT03019289PridopidineDopaminergic stabilizerHealthy individuals and HDPharmacodynamic at 1 daySingle dose, open-label, single group trial38Teva Branded Pharmaceutical Products, R&D Inc.Germany (single center)
NCT02453061TRIHEP 3TriheptanoinAnaplerotic therapyHDPlaceboPharmacodynamic efficacy at 6 monthsRandomized, double-blind, placebo-controlled, parallel trial100Institut National de la Santé Et de la Recherche Médicale, Ultragenyx Pharmaceutical Inc.France, Netherlands (multi center)
NCT02519036IONIS-HTTRXIONIS-HTTRXAntisense oligonucleotideHDPlaceboSafety and tolerability at 29 weeksRandomized, double-blind, placebo-controlled, parallel, dose ascending trial46Ionis Pharmaceuticals, Inc.Canada, Germany, UK (multi center)
NCT02509793TetrabenazineVMAT2 inhibitorHD with impulsivityCognitive and behavioral effects at 8 weeksSingle group, open-label trial20University of Texas Health Science Center, and H. Lundbeck A/SUSA (single center)
NCT02507284STAIRSRX246Vasopressin 1a Receptor AntagonistEarly and moderate HD with irritabilityPlaceboFeasibility at 12 weeksRandomized, double-blind, placebo-controlled, parallel trials108Azevan Pharmaceuticals, NINDS, & NeuroNEXT NetworkUSA (multi center)
NCT02494778Open PRIDE-HDPridopidineDopaminergic stabilizerPRIDE-HD completersSafety at 104 weeksSingle group, open label extension of PRIDE-HD300Teva Branded Pharmaceutical Products, R&D Inc.Australia, Austria, Canada, Denmark, France, Germany, Italy, Netherlands, Poland, Russia, UK, USA (multi center)
NCT02481674SIGNALVX15/2503Anti-semaphorin 4D monoclonal antibodyLate premanifest or early HDPlaceboSafety and tolerability at 15 and 21 monthsRandomized, double-blind, placebo-controlled, parallel trial116Vaccinex Inc., HSGUSA (multi center)
NCT02336633REVHDResveratrolDietary supplementHDPlaceboNeuroimaging biomarkers at 1 yearRandomized, double-blind, placebo-controlled, parallel trial102Assistance Publique –Hôpitaux de ParisFrance (multi center)
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 center)
EUCTR2013-002545-10-SEOSU6162Open1309(–)-OSU616Monoaminergic stabilizerHD, PD, brain trauma, stroke, myalgic encephalomyelitis and narcolepsy       –Safety at 3, 6 and 12 monthsSingle group, open-label trial240A. Carlsson Research ABSweden (multi center)
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 center)
NCT00632645NEUROHDOlanzapineDopamine agonistHD with motor or behavioral symptomsTetrabenazine, or tiaprideEfficacy at 12 monthsRandomized, open-label, controlled, parallel trial180Assistance Publique –Hôpitaux de Paris,France (single center)
NCT01306929OPEN-HARTPridopidineDopaminergic stabilizerHART or PRIDE-HD completersSafety at 2 yearsSingle group, open label extension of HART235Teva Branded Pharmaceutical Products, R&D Inc.Canada, USA (multi center)
NCT00514774UDCA-HDUrsodiolBile acidHDPlaceboSafety, tolerability and pharmacokinetics at 35 daysRandomized, double-blind, placebo-controlled, parallel trial21Oregon Health and Science University, HSG, Huntington Society of CanadaN/S
NCT01897896ARC-HDDeutetrabenazineVMAT2 inhibitorEarly and moderate HD with chorea on tetrabenazine or FIRST-HD completersSafety at 54 weeksSingle group, open-label, drug-switching trial238Auspex Pharmaceuticals, Inc., Teva Pharmaceutical IndustriesAustralia, Canada, USA (multi center)
ACTRN12616001611415VCAS-HDVareniclineNicotinic acid receptor partial agonistHDPlaceboEfficacy at 10 weeksRandomized, double-blind, placebo-controlled, parallel trial40University of AucklandNew Zealand (single center)
Table 2

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). DBS, deep brain stimulation; EHDN, European Huntington’s Disease Network; ET, Essential Tremor; GP, Globus pallidus; HT, Holmes Tremor; MNC, mononuclear cells; PD, Parkinson’s disease; TD, Tardive dyskinesia; WD, Wilson’s disease

Registration IDTrial nameInterventionMechanismPopulationComparisonMain outcomeStudy designEstimatedSponsorLocation
of ActionEnrolment
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 center)
NCT01834053BMACHCBone Marrow Derived MNC transplantBone marrow transplantHD with choreaCognitive and behavioral effects at 6 monthsSingle group, open-label trial50Chaitanya Hospital, PuneIndia (single center)
NCT02263430GP DBSDeep brain stimulationHD with choreaSham stimulationEfficacy at 12 monthsRandomized, double-blind, placebo-controlled, parallel trial8Beijing Pins Medical Co., Ltd, Beijing Tiantan HospitalChina (single center)
NCT02252380Magnetic Resonance Guided Focused UltrasoundExtracranial stereotactic radioablationHD, ET, HT, PD, WD, dystonia, TD, or orofacial dyskinesiasAdverse events after the procedureSingle group, open-label trial10InSightecCanada (single center)
Table 3

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

Registration IDTrial nameInterventionMechanism ofPopulationComparisonMain outcomeStudy designEstimatedSponsorLocation
ActionEnrolment
NCT02990676CogTrainHDComputerized Cognitive TrainingCognitive trainingHDNo interventionFeasibility at 4 yearsOpen-label, controlled, parallel trial50Cardiff UniversityUK (single center)
NCT01879267Endurance exercise trainingPhysiotherapyHD and healthy controlsMotor effects 6 monthsSingle group, open-label trial with parallel healthy controls arm40University of ZurichSwitzerland (single center)
NCT02464293Mindfulness-based Cognitive TherapyCognitive therapyPremanifest and early HD with behavioral symptomsBehavioral effect at 2 weeks, 3 months and 1 yearSingle group, open-label trial16Lancaster University, Central Manchester University Hospitals NHS Foundation TrustUK (single center)
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 center)
NCT02750982Laughter TherapyCognitive therapyHD, AD, ALS, brain injury, MS, PD, post/stroke or spinal cord injuryBehavioral effects at 8 weeksSingle group, open-label trial24Brown, Theodore R., M.D., MPHUSA (single center)
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 center)

LEGATO-HD (NCT02215616)

Study title: A Clinical Study in Subjects With Huntington’s Disease to Assess the Efficacy and Safety of Three Oral Doses of Laquinimod [9].

Intervention: Laquinimod, an immunomodulatory molecule [10].

Description: The LEGATO-HD trial aims to compare the efficacy and safety of laquinimod 0.5 mg qd, 1 mg qd, 1.5 mg qd, and placebo qd, for disease modification in people with HD (CAG repeat number ≥ 36 plus Unified Huntington’s Disease Rating Scale (UHDRS) Total Motor Score (TMS) >5), aged between 21 and 55 years old.

Participant involvement will last for 12 months of treatment. The trial is a phase 2, international, multi-center, randomized, placebo controlled, double blind, parallel study. The recruitment aim is 400 participants in Canada, Czech Republic, France, Germany, India, Israel, Italy, Netherlands, Portugal, Russia, Spain, United Kingdom, and United States of America.

The primary outcome is change from baseline in the UHDRS TMS after 1, 3, 6, and 12 months of treatment. The secondary outcomes involve the UHDRS Total Functional Capacity (TFC), the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) global score, the Huntington’s Disease Cognitive Assessment Battery (HD-CAB), and caudate volume.

Sponsors/funders: Teva Branded Pharmaceutical Products, R&D Inc.

Comments: Along the course of this study, due to safety concerns derived from a study of laquinimod in multiple sclerosis, the sponsor opted to stop the 1.5 mg qd dosage but maintain the others. This study is now fully recruited [11] with an expected completion date of August 2018.

IONIS-HTTRx (NCT02519036)

Study title: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS-HTTRx in Patients With Early Manifest Huntington’s Disease [12]

Intervention: IONIS-HTTRx, an antisense oligonucleotide against the huntingtin pre-messenger RNA [13].

Description: The IONIS-HTTRx trial aims to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of IONIS-HTTRx administered intrathecally, comparing with intrathecal placebo, for disease modification in people with HD, aged between 25 and 65 years old. HTTRx is an antisense oligonucleotide targeting the pre-mRNA transcript of the HTT gene in an allele-nonselective manner, with the aim of reducing the production of mutant huntingtin protein. The intervention is administered 4 times at 4 week intervals over the course of 13 weeks. The dose has ascended consecutively throughout the study.

Each participant’s involvement will last for 29 weeks. It is a phase 1b/2a, international multi-center, randomized, placebo controlled, double blind, parallel, dose-ascending study, taking place in Canada, Germany and the United Kingdom. The recruitment goal of 46 participants was reached in June2017 [14].

The primary outcome is safety and tolerability at 29 weeks. The secondary outcomes involve pharmacokinetic and pharmacodynamic measures in the cerebrospinal fluid, such as peak drug concentrations, time to peak dose concentrations, huntingtin concentration, neurofilament light concentration, and also ventricular volume and performance on the HD Cognitive Assessment Battery (HD-CAB).

Sponsors/funders: Ionis Pharmaceuticals, Inc.

Comments: This trial is currently fully recruited and an open-label extension was announced in June 2017 for the participants in the original trial.

COMPLETED CLINICAL TRIALS

Amaryllis (NCT02197130)

Study title: Randomized, Placebo Controlled Study Of The Efficacy And Safety Of PF-02545920 In Subjects With Huntington’s Disease [15].

Intervention: PF-02545920, a phosphodiesterase 10a inhibitor [16].

Description: The goal of the Amaryllis trial was to compare the efficacy and safety of PF-02545920 5 mg bid, PF-02545920 20 mg bid, and placebo bid, for symptomatic relief of motor impairment in people with early HD (CAG repeat number ≥ 36 plus UHDRS TFC ≥ 7) and chorea (UHDRS TMS ≥ 10), aged between 30 and 65 years old.

Participant involvement lasted for 26 weeks. It was a phase 2, international, multi-center, randomized, placebo controlled, double blind, parallel study conducted in Canada, Germany, Poland, United Kingdom, and United States of America. 272 participants were recruited.

The primary outcome was change from baseline in the UHDRS TMS after 26 weeks of treatment. The secondary outcomes involved the UHDRS TFC, the Clinical Global Impression-Improvement, the Columbia Suicide Severity Rating Scale (C-SSRS), extrapyramidal symptoms, and white cell counts and neutrophil counts.

Sponsors/funders: Pfizer

Results: The trial was completed on September 2016. Although the results have not been released in a peer-reviewed publication, Pfizer has officially announced that the phosphodiesterase 10a inhibitor did not meet its goals in improving motor impairment in people with HD. Indeed several other secondary outcomes remained unchanged, such as functional ability [17]. As a consequence, the ongoing 12 month-long open-label extension (NCT02342548) of PF-02545920 20 mg bid was discontinued in February 2017 [18].

Pride-HD (NCT02006472)

Study title: A Phase 2, to Evaluating the Safety and Efficacy of Pridopidine Versus Placebo for Symptomatic Treatment in Patients With Huntington’s Disease [19].

Intervention: Pridopidine, a dopaminergic stabilizer [20].

Description: Pride-HD trial aimed to compare the efficacy and safety of pridopidine 45 mg bid, 67.5 mg bid, 90 mg bid, 112.5 mg bid, and placebo bid, for symptomatic relief of motor impairment in people with HD (CAG repeat number ≥ 36 plus UHDRS Independence Score <90%) and chorea (UHDRS TMS ≥ 25), aged ≥ 21 years old.

It lasted for 52 weeks, was a phase 2, international, multi-center, randomized, placebo controlled, double blind, parallel study taking place in Australia, Austria, Canada, Czech Republic, Denmark, France, Germany, Italy, Netherlands, Poland, Russia, United Kingdom, and United States of America. It recruited 408 participants.

The primary outcome was change from baseline in the UHDRS TMS after 26 weeks of treatment. The secondary outcomes involved the modified Physical Performance Test, and adverse events. Early in the course of the study, the sponsors instituted a change in the study design, from a 26-week study focused primarily on changes in motor symptoms as measured by the TMS, to a longer 52-week study to explore pridopidine’s potential impact on functionalendpoints.

Sponsors/funders: Teva Branded Pharmaceutical Products, R&D Inc., European Huntington’s Disease Network (EHDN) and Huntington’s Study Group (HSG).

Results: The trial was completed on July 2016. On September 2016 Teva announced on its website that “pridopidine demonstrates slowing of progression of Huntington disease in Pride-HD study as measured by total functional capacity” [21]. This announcement sparked some controversy [22], since the data presented by Teva at the 9th EHDN Plenary Meeting 2016 The Hague showed that Pride-HD failed to meet its primary endpoint –change in UHDRS TMS at 26 weeks [21]. The interpretation of potential benefit hinged upon of a lack of decline in the UHDRS TFC at the extended 52-week timepoint. The effect was only significant in patients taking the lowest dose of pridopidine. The sponsor also pointed out “an unusually high placebo effect” that complicated interpretation of the findings. The Chairs of the EHDN Executive Committee issued a statement responding to Teva’s announcement, saying “there has been discussion over the statement in the press release that these results indicate that pridopidine slows down disease progression in HD. This statement needs to be read in the context of the whole document, which clearly speaks about slowing decline in functional capacity. This should not be misunderstood as a demonstration of disease modification or ofneuroprotection” [23].

Still, the final results of this study have not yet been published, and we look forward to seeing them after peer review. The open label extension of this trial— Open PRIDE-HD (NCT02494778)— is still ongoing, according to the latest public information.

CONFLICTS OF INTEREST

FBR and EJW are sub-investigators on LEGATO-HD (NCT02215616) and IONIS-HTTRx (NCT02519036), and EJW was a sub-investigator on Amaryllis (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 and Wave Life Sciences. 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.

ACKNOWLEDGMENTS

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).

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