Jamie L. Hamilton

Suicidal ideation and sleep disturbances are more common among people with Huntington disease (PwHD) than otherwise healthy peers; however, the scope and magnitude of these challenges are not well understood. This study evaluated suicidal thoughts and sleep disturbances among PwHD in Europe and the United States using data from the Huntington's Disease Burden of Illness (HDBOI) study. The HDBOI study is a cross-sectional burden-of-illness study of PwHD in France, Germany, Italy, Spain, the United Kingdom, and the United States. Eligible participants were adults (18 years and older) with motor manifest Huntington disease (HD) ≥ 12 months before study recruitment. PwHD were categorized as having early-stage (ES), mid-stage (MS), or advanced-stage (AS) HD as reported by the treating physician. Data were collected by the physician, and a voluntary questionnaire was completed by the PwHD or a caregiver. All findings were analyzed descriptively. Differences were assessed using analysis of variance or χ² tests. A total of 2,094 PwHD were included; 1,602 (77%) were from Europe and 492 (23%) were from the United States, with 846 (40%) with ES, 701 (33%) with MS, and 547 (26%) with AS HD. PwHD reported current (13%, n = 272) or previous (28%, n = 575) suicidal ideation, which was more common with advanced HD (ES, 11%; MS, 14%; AS, 15%; p < 0.05). Of 482 questionnaire respondents, 91% (n = 437) reported difficulty sleeping, which was more common with AS HD (p < 0.05; [p = 0.000]). The HDBOI study showed a substantial burden of suicidal ideation and sleep disturbances among PwHD, which tended to worsen with disease severity.

Disease-modifying treatments (DMTs) such as gene therapy are currently under investigation as a potential treatment for Huntington disease (HD). Our objective was to estimate the long-term natural history of HD progression and explore the potential efficacy impacts and value of a hypothetical DMT using a decision-analytic modeling framework. We developed a health state transition model that separately analyzed 40-year-old individuals with prefunctional decline (PFD, HD Integrated Staging System [HD-ISS] stage <3, total functional score [TFC] 13), active functional decline Shoulson and Fahn category 1 (SF1, HD-ISS stage 3, TFC 13-11), and SF2 (HD-ISS stage 3, TFC 10-7). Three-year outcomes from the TRACK-HD longitudinal study were linearly extrapolated to estimate the long-term health outcomes and costs of each population. For PFD individuals, we used the HD-ISS to predict the onset of functional decline. HD costs and quality-adjusted life years (QALYs) were estimated over a lifetime horizon by applying health state–specific costs and utilities derived from a related HD burden-of-illness study. We then estimated the long-term health impacts of hypothetical DMTs that slowed or delayed onset of functional decline. We conducted sensitivity analyses to assess model uncertainties. The expected life years for 40-year-old PFD, SF1, and SF2 populations were 20.46 (95% credible range [CR]: 19.05–22.30), 13.93 (10.82–19.08), and 10.99 (8.28–22.07), respectively. The expected QALYs for PFD, SF1, and SF2 populations were 15.93 (14.91–17.44), 8.29 (6.36–11.79), and 5.79 (4.14–12.91), respectively. The lifetime costs of HD were $508,200 ($310,300 to $803,700) for the PFD population, $1.15 million ($684,500 to $1.89 million) for SF1 individuals, and $1.07 million ($571,700 to $2.26 million) for SF2 individuals. Although hypothetical DMTs led to cost savings in the PFD population by delaying the cost burdens of functional decline, they increased costs in SF1 and SF2 populations by prolonging time spent in expensive progressive HD states. Our novel HD-modeling framework estimates HD progression over a lifetime and the associated costs and QALYs. Our approach can be used for future cost-effectiveness models as positive DMT clinical trial evidence becomes available.

Background: Minimal clinically important difference (MCID) represents the smallest within‐person change on an outcome measure considered meaningful to the patient. Anchor‐based MCID methods evaluate the relationship between changes in an outcome measure and the patient‐reported clinical importance of that change.Objective: This study aims to estimate longitudinal MCID for clinically relevant outcome measures for individuals who have Stages 2 or 3 disease as measured by the Huntington's Disease Integrated Staging System (HD‐ISS).Methods: Data were drawn from Enroll‐HD, a large global longitudinal, observational study and clinical research platform for HD family members. We analyzed HD participants (N = 11,070) by staging group using time frames ranging from 12 to 36 months. The anchor was the physical component summary score of the 12‐item short‐form health survey. HD‐relevant motor, cognitive, and functional outcome measures were independent, external criterion outcomes. Complex analysis was conducted using multiple, independent, linear mixed effect regression models with decomposition to calculate MCID for each external criterion by group.Results: MCID estimates varied by progression stage. MCID estimates increased as stage progression increased and as the time frame increased. MCID values for key HD measures are provided. For example, starting in HD‐ISS stage 2, meaningful group change over 24 months equals an average increase of 3.6 or more points on the Unified Huntington's Disease Rating Scale Total Motor Score.Conclusions: This is the first study to examine MCID estimation thresholds for HD. The results can be used to improve clinical interpretation of study outcomes and enable treatment recommendations to support clinical decision‐making and clinical trial methodology. © 2023 International Parkinson and Movement Disorder Society.