Objective: Investigate the time to the event of HD-ISS Stage 3 transition (functional change) as an endpoint for clinical trials in Huntington’s disease (HD) and present sample size estimates after applying enrichment strategies.

Background: The Huntington’s Disease Integrated Staging System (HD-ISS) characterizes progression of HD across the lifespan [1] and allows for the design of trials earlier in HD with the goal of delaying progression. Clinical trial scenarios can be modeled after applying the HD-ISS to observational studies.

Method: We combined PREDICT-HD [2], TRACK-HD/ON [3], and Enroll-HD [4] data, and classified individuals according to the HD-ISS. The system consists of 4 stages: Stage 0, CAG≥40; Stage 1, caudate and/or putamen atrophy; Stage 2, motor and/or cognitive signs; and Stage 3, functional change. Imputation of stage was performed with a machine learning method for Enroll-HD. We included patients starting in HD-ISS Stage 0, 1, or 2 (N=4011) and assessed the ability of the Prognostic Index Normed (PIN) and its components, CAP, Symbol Digit Modalities Test, and Total Motor Score [5], to predict time to Stage 3. For enrichment, we used quartiles of the baseline PIN distribution for patients in Stage 2 (N=1356) to form four groups and created survival curves by group (survival is defined as not transitioning to Stage 3). We selected enrichment subgroups closer to Stage 3 transition and estimated sample sizes for the time to Stage 3, using delay in the onset of transition (3, 6, 9 months) as the effect size.

Results: In the prediction of time to Stage 3, PIN (AUC=0.84) outperforms CAP, SDMT, and TMS (AUC=0.79, 0.79, 0.81 respectively; all p<.0001 versus PIN). Quartiles from the baseline PIN distribution (Q1=0.46, Q2=1.18, Q3=1.96) separate Stage 2 participants into four regions. [figure1] Survival curves for each group show that the two groups with PIN>1.18 have median time to Stage 3 transition of about 2 years and these are selected as enrichment subgroups. [figure2] Sample size estimates for the given scenario are presented by enrichment subgroup. [table1]

Conclusion: Our analysis shows that PIN is highly predictive of Stage 3 transition. A delay of six months or more in the onset of Stage 3 for an enriched sample yields feasible sample size estimates, demonstrating that this approach can aid in the planning of future clinical trials. A version of this abstract was presented at HDTC, Orašac, Croatia, April 24-27, 2023.

References: [1] Tabrizi SJ, Schobel S, Gantman EC, et al. A biological classification of Huntington’s disease: the Integrated Staging System. Lancet Neurol 2022;21(7):632-644. [2] Paulsen JS, Long JD, Ross CA, et al. Prediction of manifest Huntington’s disease with clinical and imaging measures: A prospective observational study. Lancet Neurol 2014;13:1193–1201. [3] Tabrizi SJ, Scahill RI, Owen G, et al. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington’s disease in the TRACK-HD study analysis of 36-month observational data. Lancet Neurol 2013;12:637–649. [4] Landwehrmeyer BG, Fitter-Attas C, Giuliano J, et al. Data analytics from Enroll-HD, a global clinical research platform for Huntington’s disease. Movement Disorder Clinical Practice. 2016;4:212–224. [5] Long JD, Langbehn DR, Tabrizi SJ, Landwehrmeyer BG, Paulsen JS, Warner J, & Sampaio C. Validation of a prognostic index for Huntington’s disease. Movement Disorders, 2017;32(2), 256-263. Note: C Sampaio and SJ Tabrizi are co-senior authors for the current work.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/transition-among-hd-iss-stages-as-an-endpoint-in-clinical-trials-for-hd/