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)

Perinatal insults and neurodevelopmental disorders may impact Huntington's disease age of diagnosis

INTRODUCTION: The age of diagnosis of Huntington's disease (HD) varies among individuals with the same HTT CAG repeat expansion size. We investigated whether early-life events, like perinatal insults or neurodevelopmental disorders, influence the diagnosis age. METHODS: We used data from 13,856 participants from REGISTRY and Enroll-HD, two large international multicenter observational studies. Disease-free survival analyses of mutation carriers with an HTT CAG repeat expansion size above and including 36 were computed through Kaplan-Meier estimates of median time until an HD diagnosis. Comparisons between groups were computed using a Cox proportional hazard survival model adjusted for CAG-repeat expansion length. We also assessed whether the group effect depended on gender and the affected parent. RESULTS: Insults in the perinatal period were associated with an earlier median age of diagnosis of 45.00 years (95%CI: 42.07–47.92) compared to 51.00 years (95%CI: 50.68–51.31) in the reference group, with a CAG-adjusted hazard ratio of 1.61 (95%CI: 1.26–2.06). Neurodevelopmental disorders were also associated with an earlier median age of diagnosis than the reference group of 47.00 years (95% CI: 43.38–50.62) with a CAG-adjusted hazard ratio of 1.42 (95%CI: 1.16–1.75). These associations did not change significantly with gender or affected parent. CONCLUSIONS: These results, derived from large observational datasets, show that perinatal insults and neurodevelopmental disorders are associated with earlier ages of diagnosis of magnitudes similar to the effects of known genetic modifiers of HD. Given their clear temporal separation, these early events may be causative of earlier HD onset, but further research is needed to prove causation

Cerebrospinal fluid flow dynamics in Huntington's disease evaluated by phase contrast MRI

Multiple targeted therapeutics for Huntington’s disease are now in clinical trials, including intrathecally-delivered compounds. Previous research suggests CSF dynamics may be altered in Huntington’s disease, which could be of paramount relevance to intrathecal drug delivery to the brain. To test this hypothesis we conducted a prospective cross-sectional study comparing people with early stage Huntington’s disease with age- and gender-matched healthy controls. CSF peak velocity, mean velocity and mean flow at the level of the cerebral aqueduct, and sub-arachnoid space in the upper and lower spine, were quantified using phase contrast MRI. We calculated Spearman’s rank correlations, and tested inter-group differences with Wilcoxon rank-sum test. Ten people with early Huntington’s disease, and 10 controls were included. None of the quantified measures was associated with potential modifiers of CSF dynamics (demographics, osmolality, and brain volumes), or by know modifiers of Huntington’s disease (age and CAG-repeat); and no significant differences were found between the two studied groups. While external validation is required, the attained results are sufficient to conclude tentatively that a clinically-relevant alteration of CSF dynamics – i.e. one that would justify dose-adjustments of intrathecal drugs – is unlikely to exist in Huntington’s disease

Morphine in acute coronary syndrome: systematic review and meta-analysis

Objective: Morphine is frequently used in acute coronary syndrome (ACS) due to its analgesic effect, it being recommended in the main cardiology guidelines in Europe and the USA. However, controversy exists regarding its routine use due to potential safety concerns. We conducted a systematic review of randomised trials (RCTs) and observational studies to synthesise the available evidence. Design: Systematic review and meta-analysis. Data sources: CENTRAL, MEDLINE, EMBASE, and trial registries. Eligibility criteria for selecting studies: We included RCTs and observational studies evaluating the impact of morphine in cardiovascular outcomes or platelet reactivity measures. Data extraction and synthesis: Data was screened, extracted, and appraised by 2 independent reviewers. The data was pooled results using a random-effects model. Outcomes included in-hospital mortality, major adverse cardiovascular events (MACE), platelet reactivity (using VerifyNow®), and bleeding, reported as relative risk (RR) with 95% confidence intervals (95% CI). We assessed the confidence in the evidence using the GRADE framework. We followed the MOOSE and PRISMA guidelines. Results: Five RCTs and 12 observational studies were included, enrolling 69,993 participants. Pooled results showed an increased risk of in-hospital mortality (RR 1.45 [95% CI 1.10-1.91], low GRADE confidence), MACE (RR 1.21, 95% CI 1.02 to 1.45), and an increased platelet reactivity at 1 and 2 hours (59.37 platelet reactivity units (PRU), 95% CI 36.04 to 82.71; 68.28 PRU, 95% CI 37.01 to 99.55; high GRADE confidence) associated with morphine. We found no significant difference in the risk of bleeding. We found no differences in subgroup analyses based on study design and ACS subtype. Conclusions: Morphine was associated with an increased risk of in-hospital mortality and MACE but the high risk of bias leads to low result confidence. There is high confidence that morphine decreases the antiplatelet effect of P2Y12 inhibitors. Registrations number: PROSPERO CRD42016036357

Rating Scales and Performance‐based Measures for Assessment of Functional Ability in Huntington's Disease Critique and Recommendations

Limitation of functional ability is a major feature of Huntington's disease (HD). The International Parkinson and Movement Disorder Society (MDS) commissioned the appraisal of the use and clinimetric properties of clinical measures of functional ability that have been applied in HD studies and trials to date, to make recommendations regarding their use based on standardized criteria. After a systematic literature search, we included a total of 29 clinical measures grouped into two categories: (1) performance‐based measures (e.g., balance, walking, and reaching/grasping), and (2) rating scales. Three performance‐based measures are rated as “recommended”: the Tinetti Mobility Test for screening of fall risk and for severity assessment of mobility in patients with manifest HD (up to stage III); the Berg Balance Scale for severity of balance impairment; and the Six‐Minute Walk Test for assessment of walking endurance (severity) in HD subjects with preserved ambulation. No rating scale targeting functional ability reached a “recommended” status either for screening or severity measurement. The main challenges identified in this review include applying widely accepted conceptual frameworks to the identified measures, the lack of validation of clinical measures to detect change over time, and absence of validated measures for upper limb function. Furthermore, measures of capacity or ability to perform activities of daily living had ceiling effects in people with early and pre‐manifest HD. We recommend that the MDS prioritize the development of new scales that capture small, but meaningful changes in function over time for outcome assessment in clinical trials, particularly in earlier stages of HD