Huntington’s disease (HD) is a progressive neurological condition. Two factors that impede clinical trials in the HD space are the slow progression of the disease that makes it difficult to detect treatment-specific changes over a relatively short period of time and the number of people wanting to know if they are carriers of the mutation.
The first factor means more HD patients are needed in a trial to obtain the statistical power to determine if a treatment is working or not. The second means that the pool of HD patients available for a clinical trial before they are symptomatic is quite small.
A new study recently published in JAMA Neurology
may have found a solution to the 2 factors limiting HD clinical trials; a change in the primary endpoint being measured.
Jeffrey Long, PhD and colleagues looked at data from 2 large clinical trials involving HD patients and, instead of looking only at motor diagnosis as a primary endpoint, examined whether progression-free survival (PFS) – composite of a motor diagnosis or a progression event could be used as an endpoint. If so, would it change the power of the trial so that less people would be needed to participate in a trial.
The researchers compared symptoms in both carriers and non-carriers of the HTT
gene mutation in 2 longitudinal cohort studies, the Track study (167 prediagnosis mutation carriers and 156 noncarriers) and the Cooperative Huntington Observational Research Trial (COHORT; 366 prediagnosis mutation carriers and 366 noncarriers).
In looking at the data and comparing motor symptoms scores vs PFS scores, the study found that PFS with a motor diagnosis or total motor score progression required about 4 times fewer people to be in the sample size to detect significant changes than when just assessing by motor diagnosis alone. The researchers also noted that by adding cognitive progression events further reduced the number. In their report, they used the example that for a a 3-year trial with 10% attrition and a treatment effect of 50%, a total of 661 would be needed if motor diagnosis was the primary endpoint. In contrast, only 177 patients would be needed if using a PFS score.
The authors concluded that the PFS end point may provide feasible sample sizes for clinical trial planning for Huntington disease gene expansion mutation carriers who have not yet received a motor diagnosis.
This conclusion is important given that a diagnosis of HD is largely based on the Unified Huntington’s Disease Rating Scale (UHDRS), which is a motor diagnosis and one that does not occur until motor symptoms are quite apparent. Using a PFS assessment would increase the pool of HD patients available to participate in a trial prior to an official diagnosis (i.e., carriers of the HTT gene mutation who may appear asymptomatic) and also allow for fewer people needed to enter a trial.
Long JD, Mills JA, Leavitt BR, et al. Survival End Points for Huntington Disease Trials Prior to a Motor Diagnosis. JAMA Neurol. 2017;
Published online ahead of print. doi:10.1001/jamaneurol.2017.2107.