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JAMA Neurol. 2017 Nov 1;74(11):1352-1360. doi: 10.1001/jamaneurol.2017.2107.

Survival End Points for Huntington Disease Trials Prior to a Motor Diagnosis.

Author information

1
Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City.
2
Department of Biostatistics, Carver College of Medicine, University of Iowa, Iowa City.
3
Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
4
Department of Genetics and Cytogenetics, and INSERM UMR S679, Institut du Cerveau et de la Moelle Epinière, Hôpital de la Salpêtrière, Paris, France.
5
Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands.
6
School of Psychology and Psychiatry, Monash University, Melbourne, Victoria, Australia.
7
Department of Neurology, University of Münster, Münster, Germany.
8
Cure Huntington's Disease Initiative Foundation, Department of Neurology, University of Ulm, Ulm, Germany.
9
Huntington's Disease Research Centre, Institute of Neurology, University College London, London, England.
10
Institute of Neurology, University College London, London, England.
11
Huntington's Disease Centre, Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London, England.

Abstract

Importance:

Predictive genetic testing in Huntington disease (HD) enables therapeutic trials in HTT gene expansion mutation carriers prior to a motor diagnosis. Progression-free survival (PFS) is the composite of a motor diagnosis or a progression event, whichever comes first.

Objective:

To determine if PFS provides feasible sample sizes for trials with mutation carriers who have not yet received a motor diagnosis.

Design, Setting, and Participants:

This study uses data from the 2-phase, longitudinal cohort studies called Track and from a longitudinal cohort study called the Cooperative Huntington Observational Research Trial (COHORT). Track had 167 prediagnosis mutation carriers and 156 noncarriers, whereas COHORT had 366 prediagnosis mutation carriers and noncarriers. Track studies were conducted at 4 sites in 4 countries (Canada, France, England, and the Netherlands) from which data were collected from January 17, 2008, through November 17, 2014. The COHORT was conducted at 38 sites in 3 countries (Australia, Canada, and the United States) from which data were collected from February 14, 2006, through December 31, 2009. Results from the Track data were externally validated with data from the COHORT. The required sample size was estimated for a 2-arm prediagnosis clinical trial. Data analysis took place from May 1, 2016, to June 10, 2017.

Main Outcomes and Measures:

The primary end point is PFS. Huntington disease progression events are defined for the Unified Huntington's Disease Rating Scale total motor score, total functional capacity, symbol digit modalities test, and Stroop word test.

Results:

Of Track's 167 prediagnosis mutation carriers, 93 (55.6%) were women, and the mean (SD) age was 40.06 (8.92) years; of the 156 noncarriers, 87 (55.7%) were women, and the mean (SD) age was 45.58 (10.30) years. Of the 366 COHORT participants, 229 (62.5%) were women and the mean (SD) age was 42.21 (12.48) years. The PFS curves of the Track mutation carriers showed good external validity with the COHORT mutation carriers after adjusting for initial progression. For required sample size, PFS with a motor diagnosis or total motor score progression required about 4 times fewer participants than a motor diagnosis alone. Including additional cognitive progression events further reduced the number. For example, a 3-year trial with 10% attrition and a treatment effect of 50% requires a total of 661 with motor diagnosis as the survival end point but only 177 with a total motor score PFS.

Conclusions and Relevance:

Reasonably sized prediagnosis Huntington disease trials can be planned with PFS, and there is evidence of generalizability of this approach.

PMID:
28975278
PMCID:
PMC5710578
DOI:
10.1001/jamaneurol.2017.2107
[Indexed for MEDLINE]
Free PMC Article

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