Huntington's Disease Clinical Trials Corner: August 2018.
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ABSTRACT:
SUBMITTER: Rodrigues FB
PROVIDER: S-EPMC6087448 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Huntington's Disease Clinical Trials Corner: August 2018.
Rodrigues Filipe B FB Wild Edward J EJ
Journal of Huntington's disease 20180101 3
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). ...[more]
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Project description:In this edition of the Huntington's Disease Clinical Trials Corner we expand on the HD-DBS and on the TRIHEP3 trials, and we list all currently registered and ongoing clinical trials in Huntington's disease.
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Project description:In the second edition of the Huntington’s Disease Clinical Trials Corner we list all currently registered and ongoing clinical trials, summarise the top-line results of the recently-announced IONIS-HTTRX trial (NCT02519036), expand on Wave Life Sciences’ PRECISION-HD1 (NCT03225833) and PRECISION-HD2 (NCT03225846), and cover one recently finished trial: the FIRST-HD deutetrabenazine trial (NCT01795859).
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Project description: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.
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Project description:BackgroundHuntington's disease (HD) develops in individuals with extended cytosine-adenine-guanine (CAG) repeats within the huntingtin (HTT) gene, causing neurodegeneration and progressive motor and cognitive symptoms. The inclusion of mutant HTT carriers in whom overt symptoms are not yet fully manifest in therapeutic trials would enable the development of treatments that delay or halt the accumulation of significant disability.ObjectivesThe present analyses assess whether screening prediagnosis (preHD) individuals based on a normalized prognostic index (PIN) score would enable the selection of prodromal preHD subjects in whom longitudinal changes in established outcome measures might provide robust signals. It also compares the relative statistical effect size of longitudinal change for these measures.MethodsIndividual participant data from 2 studies were used to develop mixed effect linear models to assess longitudinal changes in clinical metrics for participants with preHD and PIN-stratified subcohorts. Relative effect sizes were calculated in 5 preHD studies and internally normalized to evaluate the strength and consistency of each metric across cohorts.ResultsLongitudinal modeling data demonstrate the amplification of effect sizes when preHD subcohorts were selected by PIN score thresholds of >0.0 and >0.4. These models and relative effect sizes across 5 studies consistently indicate that the Unified Huntington's Disease Rating Scale total motor score exhibits the greatest change in preHD.ConclusionsThese analyses suggest that the employment of PIN scores to homogenize and stratify preHD cohorts could improve the efficiency of current outcome measures, the most robust of which is the total motor score. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Project description:While there is no known cure for Huntington's disease (HD), there are early-phase clinical trials aimed at altering disease progression patterns. There is, however, no obvious single outcome for these trials to evaluate treatment efficacy. Currently used outcomes are, while reasonable, not optimal in any sense. In this paper we derive a method for constructing a composite variable via a linear combination of clinical measures. Our composite variable optimizes the signal-to-noise ratio (SNR) within the context of a longitudinal study design. We also demonstrate how to induce sparsity using a soft-approximation of an L 1 penalty on the coefficients of the composite variable. We applied our method to data from the TRACK-HD study, a longitudinal study aimed at establishing good outcome measures for HD, and found that compared to the existing composite measurement our composite variable provides a larger SNR and allows clinical trials with smaller sample sizes to achieve equivalent power.
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Project description:BackgroundHuntington's disease like 2 (HDL2) is the most common Huntington's disease (HD) phenocopy in many countries and described as the phenocopy with the greatest resemblance to HD. The current clinical description of HDL2 is based on retrospective data. It is unknown whether HDL2 has clinical features that distinguish it from HD.ObjectiveTo describe the HDL2 phenotype and compare it to HD systematically.MethodsA blinded cross-sectional design was used to compare the HDL2 (n = 15) and HD (n = 13) phenotypes. African ancestry participants underwent assessments, including the Unified Huntington's Disease Rating Scale (UHDRS). The UHDRS motor component was video recorded and evaluated by blinded experts and the inter-rater reliability calculated.ResultsBoth groups were homogeneous in terms of demographics and disease characteristics. However, HDL2 patients presented three years earlier with more prominent dysarthria and dystonia. Raters could not distinguish between the two diseases with a high level of agreement. No significant differences in the TMS between HDL2 and HD were found. In both disorders, disease duration correlated with motor scores, with the exception of chorea. Psychiatric and cognitive scores were not significantly different between the groups.ConclusionsThe HDL2 phenotype is similar to HD and is initially characterized by dementia, chorea, and oculomotor abnormalities, progressing to a rigid and bradykinetic state, suggesting the UHDRS is useful to monitor disease progression in HDL2. Although HDL2 patients scored higher on some UHDRS domains, this did not differentiate between the two diseases; it may however be emerging evidence of HDL2 having a more severe clinical phenotype.
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Project description:Irritability, together with depression and anxiety, form three salient clinical features of pre-symptomatic Huntington's disease (HD). To date, the understanding of irritability in HD suffers from a paucity of experimental data and is largely based on questionnaires or clinical anecdotes. Factor analysis suggests that irritability is related to impulsivity and aggression and is likely to engage the same neuronal circuits as these behaviours, including areas such as medial orbitofrontal cortex (OFC) and amygdala. 16 pre-symptomatic gene carriers (PSCs) and 15 of their companions were asked to indicate the larger of two squares consecutively shown on a screen while undergoing functional magnetic resonance imaging (fMRI). Despite correct identification of the larger square, participants were often told that they or their partner had given the wrong answer. Size differences were subtle to make negative feedback credible but detectable. Although task performance, baseline irritability, and reported task-induced irritation were the same for both groups, fMRI revealed distinct neuronal processing in those who will later develop HD. In controls but not PSCs, task-induced irritation correlated positively with amygdala activation and negatively with OFC activation. Repetitive negative feedback induced greater amygdala activations in controls than PSCs. In addition, the inverse functional coupling between amygdala and OFC was significantly weaker in PSCs compared to controls. Our results argue that normal emotion processing circuits are disrupted in PSCs via attenuated modulation of emotional status by external or internal indicators. At later stages, this dysfunction may increase the risk for developing recognised, HD-associated, psychiatric symptoms such as irritability.
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Project description:In July 2018, a large outbreak of Legionnaires' disease (LD) caused by Legionella pneumophila serogroup 1 (Lp1) occurred in Bresso, Italy. Fifty-two cases were diagnosed, including five deaths. We performed an epidemiological investigation and prepared a map of the places cases visited during the incubation period. All sites identified as potential sources were investigated and sampled. Association between heavy rainfall and LD cases was evaluated in a case-crossover study. We also performed a case-control study and an aerosol dispersion investigation model. Lp1 was isolated from 22 of 598 analysed water samples; four clinical isolates were typed using monoclonal antibodies and sequence-based typing. Four Lp1 human strains were ST23, of which two were Philadelphia and two were France-Allentown subgroup. Lp1 ST23 France-Allentown was isolated only from a public fountain. In the case-crossover study, extreme precipitation 5-6 days before symptom onset was associated with increased LD risk. The aerosol dispersion model showed that the fountain matched the case distribution best. The case-control study demonstrated a significant eightfold increase in risk for cases residing near the public fountain. The three studies and the matching of clinical and environmental Lp1 strains identified the fountain as the source responsible for the epidemic.
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Project description:BACKGROUND:Advances in molecular therapeutic approaches in the last decade are translating into the design of non-traditional clinical trials. In order to improve their feasibility, it is important to understand the attitudes of potential participants towards these trials, their motivations to get involved and acceptance of risks. OBJECTIVE:We aimed to better understand the willingness of potential participants to participate in different molecular therapy trials for Huntington's disease (HD) based on their clinical and genetic status, trial design and goals of the treatment. METHODS:An anonymous survey was distributed through the Huntington's Disease Society of America (HDSA) on-line portal/website. Various hypothetical scenarios were presented followed by a survey consistent of Likert scale responses ascertaining willingness to participate, collecting demographic, clinical and genetic information. RESULTS:There were a total of 87 responses, including patients diagnosed with HD, pre-manifesting mutation carriers and asymptomatic participants at risk. The majority of participants indicated they were very likely or likely to participate in clinical trials independent of study design or goals of the therapy, with a more favorable view in premanifesting mutation carriers. However, more invasive procedures and trials including placebo were less favorably viewed across all diagnostic groups. CONCLUSIONS:In summary, most individuals in the HD community would consider participation in novel molecular therapy trials, but study design and goals could impact patient recruitment. This data can be used to inform the recruitment and consent process into clinical trials and to address common concerns by potential participants.
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