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J04 Benchmarking enroll-HD to a phase III placebo cohort from generation HD1 to inform clinical trial planning
  1. Hannah Furby1,
  2. Athanasios Siadimas2,
  3. Peter McColgan1,
  4. Lauren Boak2,
  5. Letizia Polito2,
  6. Eileen Neacy3,
  7. Jeffrey D Long4,
  8. Cristina Sampaio3
  1. 1Roche Products Ltd, Welwyn Garden City, UK
  2. 2F. Hoffmann-La Roche Ltd, Basel, Switzerland
  3. 3CHDI Management/CHDI Foundation, Princeton, NJ, USA
  4. 4University of Iowa, Iowa City, IA, USA


Background Where a sufficiently powered placebo-controlled clinical study is a challenge, it may be possible to use external natural history data as a comparator arm (‘external control’) to determine treatment efficacy.1

Aim To establish feasibility of using Enroll-HD as an external control by benchmarking it to the placebo arm of the GENERATION HD1 (NCT03761849) study.

Methods/Techniques GENERATION HD1 inclusion criteria were applied to construct a comparable cohort from Enroll-HD. Nearest-neighbour propensity-score matching and inverse probability weighting (IPTW-ATT) methods were implemented to balance baseline characteristics between GENERATION HD1 and Enroll-HD cohorts. Regression models computed differences in annual decline of cUHDRS, TFC, TMS, SDMT, SWRT for both GENERATION HD1 placebo and Enroll-HD cohorts after controlling for CAP, CAG, age and baseline performance.

Results/Outcome Both methods balanced baseline characteristics between participants in the Enroll-HD cohort and the GENERATION HD1 placebo (standardised mean difference <0.1). Superior covariate balance was achieved by IPTW-ATT (Figure 1). One-year clinical decline was greater in the Enroll-HD cohort compared with the GENERATION HD1 placebo arm (Figure 2).

Abstract J04 Figure 1

Differences in baseline characteristics of an Enroll-HD cohort compared with GENERATION HD1 placebo data before and after covariate balancing with nearest-neighbour matching or propensity score weighting (IPTW-ATT) methods

Abstract J04 Figure 2

Clinical decline over 1 year of cUHDRS, TFC, TMS, SDMT and SWRT in the Enroll-HD cohort before (blue) after (IPTW-ATT; red) cohort balancing compared with GENERATION HD1 placebo (dotted line)

Conclusions Faster clinical decline in the Enroll-HD cohort compared with the GENERATION HD1 placebo arm has implications for the feasibility of using Enroll-HD as an external comparator in drug trials, since this could erroneously inflate the observed treatment effect. Slower decline in the placebo arm may be attributed to placebo effect and selection bias. Future work should explore the consistency of findings across placebo arms in Huntington’s disease trials and consider how best to utilise external data to enrich placebo cohorts.


  1. Jahanshahi M, Gregg K, Davis G, Ndu A, Miller V, Vockley J, et al. The Use of External Controls in FDA Regulatory Decision Making. Therapeutic Innovation & Regulatory Science 2021;55:1019-35.

  • Huntington’s disease
  • HD
  • Enroll-HD
  • Clinical trial

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