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
Trial name | Intervention | Edition | |
NCT02519036 | IONIS-HTTRx | IONIS-HTTRx* | September 2017(3) |
NCT02215616 | LEGATO-HD | Laquinimod | |
NCT02197130 | Amaryllis | PF-02545920 | |
NCT02006472 | PRIDE-HD | Pridopidine | |
NCT03225833 | PRECISION-HD1 | WVE-120101 | February 2018(33) |
NCT03225846 | PRECISION-HD2 | WVE-120102 | |
NCT01795859 | FIRST-HD | Deutetrabenazine | |
NCT02481674 | SIGNAL | VX15/2503 | August 2018(34) |
NCT00712426 | CREST-E | Creatine | |
NCT03761849 | GENERATION-HD1 | RG6042* | January 2018 |
NCT03344601 | PACE-HD | Physical 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
Registration ID | Trial name | Intervention | Mechanism of Action | Population | Comparison | Main outcome | Study design | Estimated Enrolment | Sponsor | Location |
NCT03761849* | GENERATION-HD1 | RG6042 | Allele-nonselective antisense oligonucleotide | HD | Placebo | Clinical efficacy at 101 weeks | Randomized, double-blind, placebo-controlled, parallel trial | 660 | Hoffmann-La Roche | USA, Canada, Europe (multi centre) |
NCT03787758* | – | SAGE-718 | NMDA positive allosteric modulator | HD | Placebo | Safety at 21 days | Randomized, double-blind, placebo-controlled, multiple ascending dose trial | 10 | Sage Therapeutics | N/S |
NCT03575676* | – | SOM3355 | VMAT2 inhibitor and β1 antagonist | Early and moderate HD with chorea | Placebo | Chorea at 6 months | Randomized, double-blind, placebo-controlled, cross-over trial | 30 | SOM Biotech SL | Spain (multi centre) |
NCT03515213* | – | Fenofibrate | PPARα agonist | HD | Placebo | Pharmacodynamics at 6 months | Randomized, double-blind, placebo-controlled, parallel trial | 20 | University of California, Irvine | USA (single centre) |
NCT03764215* | Tasigna HD | Nilotinib | Selective Bcr-Abl tyrosine kinase inihbitor | HD | None | Safety, tolerability and pharmacodynamics at 3 months | Open label, multiple ascending dose | 20 | Georgetown University | USA (single centre) |
NCT03342053 | IONIS-HTTRX OLE | ISIS 443139 | Allele-nonselective antisense oligonucleotide | HD | None | Safety and tolerability at 74 weeks | Open label extension | 46 | Ionis Pharmaceuticals Inc. | Canada, Germany and UK (multi-centre) |
NCT03225833 | PRECISION-HD1 | WVE-120102 | Allele-selective antisense oligonucleotide | HD | Placebo | Safety and tolerability at 1 and 120 days | Randomized, double-blind, placebo-controlled, combined single ascending dose/multiple ascending dose trial | 48 | Wave Life Sciences Ltd. | Canada and Poland (multi-centre) |
NCT03225846 | PRECISION-HD2 | WVE-120102 | Allele-selective antisense oligonucleotide | HD | Placebo | Safety and tolerability at 1 and 120 days | Randomized, double-blind, placebo-controlled, combined single ascending dose/multiple ascending dose trial | 48 | Wave Life Sciences Ltd. | Canada and Poland (multi-centre) |
NCT02453061 | TRIHEP 3 | Triheptanoin | Anaplerotic therapy | HD | Placebo | Pharmacodynamic efficacy at 6 months | Randomized, double-blind, placebo-controlled, parallel trial | 100 | Institut National de la Santé Et de la Recherche Médicale, Ultragenyx Pharmaceutical Inc | France, Netherlands (multi centre) |
NCT02509793 | – | Tetrabenazine | VMAT2 inhibitor | HD with impulsivity | None | Cognitive and behavioural effects at 8 weeks | Single group, open-label trial | 20 | University of Texas Health Science Center, and H. Lundbeck A/S | USA (single centre) |
NCT02507284 | STAIR | SRX246 | Vasopressin 1a Receptor Antagonist | Early and moderate HD with irritability | Placebo | Feasibility at 12 weeks | Randomized, double-blind, placebo-controlled, parallel trials | 108 | Azevan Pharmaceuticals, National Institute of Neurological Disorders and Stroke (NINDS), and NeuroNEXT Network | USA (multi centre) |
NCT02481674 | SIGNAL | VX15/2503 | Anti-semaphorin 4D monoclonal antibody | Late premanifest or early HD | Placebo | Safety and tolerability at 15 and 21 months | Randomized, double-blind, placebo-controlled, parallel trial | 240 | Vaccinex Inc., Huntington Study Group | USA (multi centre) |
NCT02336633 | REVHD | Resveratrol | Dietary supplement | HD | Placebo | Neuroimaging biomarkers at 1 year | Randomized, double-blind, placebo-controlled, parallel trial | 102 | Assistance Publique - Hôpitaux de Paris | France (multi centre) |
EUCTR2013-002545-10-SE | OSU6162 Open1309 | (–)-OSU616 | Monoaminergic stabilizer | HD, PD, brain trauma, stroke, myalgic encephalomyelitis and narcolepsy | None | Safety at 3, 6 and 12 months | Single group, open-label trial | 240 | A. Carlsson Research AB | Sweden (multi centre) |
NCT00514774 | UDCA-HD | Ursodiol | Bile acid | HD | Placebo | Safety, tolerability and pharmacokinetics at 35 days | Randomized, double-blind, placebo-controlled, parallel trial | 21 | Oregon Health and Science University, Huntington Study Group, Huntington Society of Canada | N/S |
ACTRN126- 16001611415 | VCAS-HD | Varenicline | Nicotinic acid receptor partial agonist | HD | Placebo | Efficacy at 10 weeks | Randomized, double-blind, placebo-controlled, parallel trial | 40 | University of Auckland | New 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
Registration ID | Trial name | Intervention | Mechanism of Action | Population | Comparison | Main outcome | Study design | Esimated Enrolment | Sponsor | Location |
ISRCTN52651778* | TRIDENT | Foetal stem cell transplant | Stem cell therapy | Early stage HD | Usal care | Safety at 4 weeks | Randomized, open label, controlled, parallel trial | 30 | Cardiff University | UK (single centre) |
NCT02728115* | SAVE-DH | Cellavita | Stem cell therapy | HD | None | Safety at 5 years | Non-randomized, open label, uncontrolled, parallel trial | 6 | Azidus Brasil | Brazil (single centre) |
NCT03252535 | ADORE-HD | Cellavita | Stem cell therapy | HD | Placebo | Efficacy at 120 days | Randomized, double-blind, placebo-controlled, parallel trial | 35 | Azidus Brasil | Brazil (single centre) |
NCT03297177 | – | Autologous stem/stromal cells | Autologous stem/stromal cell injection | HD, AD, PD, CBD, MS | None | Safety at 5 years | Single group, open-label trial | 300 | Healeon Medical Inc, Global Alliance for Regenerative Medicine, Regeneris Medical | USA and Honduras (multi-centre) |
NCT02535884 | HD-DBS | GP DBS | Deep brain stimulation | Moderate HD with chorea | Sham intervention | Efficacy at 12 months | Randomized, double-blind, sham-controlled, parallel trial | 50 | Heinrich-Heine University, KKS Netzwerk, Medtronic, The George Institute, EHDN, CHDI Foundation, Inc. | Austria, Germany, Switzerland (multi centre) |
NCT01834053 | BMACHC | Bone Marrow Derived MNC transplant | Bone marrow transplant | HD with chorea | None | Cognitive and behavioural effects at 6 months | Single group, open-label trial | 50 | Chaitanya Hospital, Pune | India (single centre) |
NCT02263430 | – | GP DBS | Deep brain stimulation | HD with chorea | Sham stimulation | Efficacy at 12 months | Randomized, double-blind, placebo-controlled, parallel trial | 8 | Beijing Pins Medical Co., Ltd, Beijing Tiantan Hospital | China (single centre) |
NCT02252380 | – | Magnetic Resonance Guided Focused Ultrasound | Extracranial stereotactic radioablation | HD, ET, HT, PD, WD, dystonia, TD, or orofacial dyskinesias | None | Adverse events after the procedure | Single group, open-label trial | 10 | InSightec | Canada (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
Registration ID | Trial name | Intervention | Mechanism of Action | Population | Comparison | Main outcome | Study design | Esimated Enrolment | Sponsor | Location |
ACTRN1261800 1717246* | – | Multidisciplinary therapy program | Exercise, cognitive training, lifestyle guidance and social activities | PremanifestHD | Standard of care | Feasability and safety | Clustered, non-randomized, open label, parallel trial | 40 | Edith Cowan University, Deakin University and Lotterywest | Australia (two centres) |
NCT03417583* | – | Neuropsychiatric treatment protocol | Multidisciplinary intervention | HD with neuropsychiatric symptoms | Standard of care | Change in quality of life at 18 months | Non-randomized, assessor-blinded, parallel trial | 100 | Vanderbilt University Medical Center and Teva Pharmaceuticals USA | USA (single centre) |
CTRI/2018/01/011359 | – | Repetitive transcranial magnetic stimulation | Transcranial magnetic stimulation | Early to moderate HD and PD | Sham stimulation | Efficacy at 5 days | Randomized, single-blind, placebo-controlled, parallel trial | 40 | Vinay Goyal | India (single centre) |
NCT03344601 | PACE-HD | Supported structured aerobic exercise training program | Physiotherapy | HD | Activity as usual | Data completeness, recruitment, retention, safety, adherence, fidelity and acceptability at 12 months | Nested open-label, randomized controlled parallel trial | 120 | Cardiff University and CHDI Foundation, Inc | Germany, Spain and USA (multi centre) |
NCT03306888 | – | Physical Activity Coaching Intervention | Physiotherapy | Premanifest and early HD | None | Change in physical activity at 4 months | Single group, open-label trial | 14 | Columbia University | USA (single centre) |
ACTRN1261700 1269325 | – | Swallowing skill training | Speech and language therapy | HD and ALS | None | Swallowing function and quality of life at 2 weeks | Single group, open-label trial | 54 | University of Canterbury | New Zealand (single centre) |
NCT02990676 | CogTrainHD | Computerised Cognitive Training | Cognitive training | HD | No intervention | Feasibility at 4 years | Open-label, controlled, parallel trial | 50 | Cardiff University | UK (single centre) |
NCT02464293 | – | Mindfulness-based Cognitive Therapy | Cognitive therapy | Premanifest and early HD with behavioural symptoms | None | Behavioural effect at 2 weeks, 3 months and 1 year | Single group, open-label trial | 16 | Lancaster University, Central Manchester University Hospitals NHS Foundation Trust | UK (single centre) |
NCT02216474 | – | tDCS | Transcranial magnetic stimulation | HD or Tourette Syndrome | Sham stimulation | Efficacy at 2 weeks | Randomized, double-blind, placebo-controlled, cross-over trial | 100 | Birmingham and Solihull Mental Health NHS Foundation Trust, University of Birmingham | UK (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 2–4.
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
CAG | Minimum age |
36 | Ineligible |
37 | Ineligible |
38 | Ineligible |
39 | Ineligible |
40 | 63.09 |
41 | 54.50 |
42 | 47.96 |
43 | 42.83 |
44 | 38.68 |
45 | 35.27 |
46 | 32.41 |
47 | 29.99 |
48 | 27.89 |
49 | 26.08 |
50 or over | 25 |
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).
REFERENCES
[1] | 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) . |
[2] | Cardiff University, CHDI Foundation Inc. PHysical Activity and Exercise Outcomes in Huntington’s Disease. https://ClinicalTrials.gov/show/NCT03344601; (2018) . |
[3] | Rodrigues FB , Wild EJ . Clinical Trials Corner: September 2017. Journal of Huntingtons Disease. (2017) ;6: (3):255–63. |
[4] | Reilmann R , McGarry A , Grachev ID , Savola J-M , Borowsky B , Eyal E , et al. Safety and efficacy of pridopidine in patients with Huntington’s disease (PRIDE-HD): A phase 2, randomised, placebo-controlled, multicentre, dose-ranging study. Lancet Neurology. (2018) . |
[5] | de Yebenes JG , Landwehrmeyer B , Squitieri F , Reilmann R , Rosser A , Barker RA , et al. Pridopidine for the treatment of motor function in patients with Huntington’s disease (MermaiHD): A phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurology. (2011) ;10: (12):1049–57. |
[6] | Huntington Study Group HART Investigators. A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington’s disease. Movement Disorders. (2013) ;28: (10):1407–15. |
[7] | Lundin A , Dietrichs E , Haghighi S , Goller ML , Heiberg A , Loutfi G , et al. Efficacy and safety of the dopaminergic stabilizer Pridopidine (ACR16) in patients with Huntington’s disease. Clinical Neuropharmacol. (2010) ;33: (5):260–4. |
[8] | Wild EJ , Tabrizi SJ . Therapies targeting DNA and RNA in Huntington’s disease. Lancet Neurology. (2017) ;16: (10):837–47. |
[9] | HDSA. RG6042 GENERATION HD1 Study: Expected Sites in USA & Canada 2018 [Available from: https://hdsa.org/wp-content/uploads/2018/12/RG6042-GENERATION-HD1-Study-update-12.19.2018.pdf. |
[10] | Schobel SA , Palermo G , Auinger P , Long JD , Ma S , Khwaja OS , et al. Motor, cognitive, and functional declines contribute to a single progressive factor in early HD. Neurology. (2017) ;89: (24):2495–502. |
[11] | Schobel S , Palermo G , Trundell D , Kremer T , Sanwald-Ducray P , Smith A , et al. editors. A Global Development Program Testing RG6042, an Antisense Oligonucleotide, for the Treatment of Early Manifest Huntington’s Disease. European Huntington’s Disease Network 2018 Plenary Meeting; 2018 14-16 September 2018; Vienna, Austria. |
[12] | Ionis Pharmaceuticals I. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS-HTTRx in Patients With Early Manifest Huntington’s Disease. https://ClinicalTrials.gov/show/NCT02519036; (2015) . |
[13] | Ionis Pharmaceuticals I. Study in Huntington’s Disease Patients Who Participated in Prior Investigational Studies of ISIS 443139. https://ClinicalTrials.gov/show/NCT03342053; (2017) . |
[14] | 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) . |
[15] | Tabrizi S , Leavitt B , Kordasiewicz H , Czech C , Swayze E , Norris DA , et al. Effects of IONIS-HTTRx in patients with early huntington’s disease, results of the first HTT-lowering drug trial. Neurology. (2018) ;90. |
[16] | Hooper G , Trundell D , Palermo G , Kremer T , Frick E , Boak L , et al. Design of a prospective, longitudinal, natural history study in huntington disease. Neurotherapeutics. (2018) ;15: (4):1182–3. |
[17] | Long JD , Landwehrmeyer B , Palermo G , Schobel S , Tabrizi SJ . Enrichment strategy in early-to-moderate manifest huntington disease based on CAG/Age product (CAP) >400 threshold. Neurotherapeutics. (2018) ;15: (4):1186. |
[18] | National Institute for Health and Care Excellence. Parkinson’s disease in adults (NG71) 2017 [Available from: nice.org.uk/guidance/ng71. |
[19] | National Institute for Health and Care Excellence. Multiple sclerosis in adults: Management (CG186) 2014 [Available from: nice.org.uk/guidance/cg186. |
[20] | Harrison DJ , Busse M , Openshaw R , Rosser AE , Dunnett SB , Brooks SP . Exercise attenuates neuropathology and has greater benefit on cognitive than motor deficits in the R6/1 Huntington’s disease mouse model. Experimental Neurology. (2013) ;248: :457–69. |
[21] | Stefanko DP , Shah VD , Yamasaki WK , Petzinger GM , Jakowec MW . Treadmill exercise delays the onset of non-motor behaviors and striatal pathology in the CAG140 knock-in mouse model of Huntington’s disease. Neurobiology of Disease. (2017) ;105: :15–32. |
[22] | Busse M , Quinn L , Debono K , Jones K , Collett J , Playle R , et al. A randomized feasibility study of a 12-week community-based exercise program for people with Huntington’s disease. Journal of Neurologic Physical Therapy. (2013) ;37: (4):149–58. |
[23] | Quinn L , Debono K , Dawes H , Rosser AE , Nemeth AH , Rickards H , et al. Task-specific training in Huntington disease: A randomized controlled feasibility trial. Physical Therapy. (2014) ;94: (11):1555–68. |
[24] | Quinn L , Hamana K , Kelson M , Dawes H , Collett J , Townson J , et al. A randomized, controlled trial of a multi-modal exercise intervention in Huntington’s disease. Parkinsonism & Related Disorders. (2016) ;31: :46–52. |
[25] | Busse M , Quinn L , Drew C , Kelson M , Trubey R , McEwan K , et al. Physical activity self-management and coaching compared to social interaction in huntington disease: Results from the ENGAGE-HD randomized, controlled pilot feasibility trial. Physical Therapy. (2017) ;97: (6):625–39. |
[26] | Thompson JA , Cruickshank TM , Penailillo LE , Lee JW , Newton RU , Barker RA , et al. The effects of multidisciplinary rehabilitation in patients with early-to-middle-stage Huntington’s disease: A pilot study. European Journal of Neurology. (2013) ;20: (9):1325–9. |
[27] | Piira A , van Walsem MR , Mikalsen G , Nilsen KH , Knutsen S , Frich JC . Effects of a one year intensive multidisciplinary rehabilitation program for patients with huntington’s disease: A prospective intervention study. PLoS Currents. (2013) ;5. |
[28] | Piira A , van Walsem MR , Mikalsen G , Oie L , Frich JC , Knutsen S . Effects of a two-year intensive multidisciplinary rehabilitation program for patients with huntington’s sisease: A prospective intervention study. PLoS Currents. (2014) ;6. |
[29] | Ciancarelli I , De Amicis D , Di Massimo C , Sandrini G , Pistarini C , Carolei A , et al. Influence of intensive multifunctional neurorehabilitation on neuronal oxidative damage in patients with Huntington’s disease. Functional Neurology. (2015) ;30: (1):47–52. |
[30] | Cruickshank TM , Thompson JA , Dominguez DJ , Reyes AP , Bynevelt M , Georgiou-Karistianis N , et al. The effect of multidisciplinary rehabilitation on brain structure and cognition in Huntington’s disease: An exploratory study. Brain and Behavior. (2015) ;5: (2):e00312. |
[31] | Fritz NE , Rao AK , Kegelmeyer D , Kloos A , Busse M , Hartel L , et al. Physical therapy and exercise interventions in huntington’s disease: A mixed methods systematic review. Journal of Huntingtons Disease. (2017) ;6: (3):217–35. |
[32] | Quinn L , Busse M , Carrier J , Fritz N , Harden J , Hartel L , et al. Physical therapy and exercise interventions in Huntington’s disease: A mixed methods systematic review protocol. JBI Database of Systematic Reviews and Implementation Reports. (2017) ;15: (7):1783–99. |
[33] | Rodrigues FB , Wild EJ . Huntington’s Disease Clinical Trials Corner: February 2018. Journal of Huntingtons Disease. (2018) ;7: (1):89–98. |
[34] | Rodrigues FB , Wild EJ . Huntington’s Disease Clinical Trials Corner: August 2018. Journal of Huntingtons Disease. (2018) ;7: (3):279–86. |