Preparing for Preventive Clinical Trials: The Predict-HD study

HD Lighthouse Contributing Editor's Comment: Part of the strategic plan for making Huntington's Disease a preventable and treatable disorder involves documenting the biological changes that occur as gene positive people near onset.

First, we need to be able to shorten clinical trials. HD is a slowly progressive disease. While we're all glad there are many years in which to enjoy quality of life, this also means that clinical trials take longer than we would like. The CARE-HD trial of CoQ10 and remacemide which ended in 2001 followed trial participants for 30 months. The 2-CARE trial is planned for 60 months, although if significant results are achieved sooner, it will be ended sooner. The alternative to long trials is to find and validate biomarkers of progression which can be used as surrogates for clinical measures. Then trials will be shorter and less expensive. More trials can be held and any treatments which result will get to people with the gene sooner.

The second reason that we need this kind of study is because people who are gene positive but not symptomatic and their doctors will need to know when to start treatments. Any drug will have side effects and there is no sense in starting one before it's needed.

The third reason is that as we learn more about HD disease pathology, we are likely to find that different treatments work during different periods of time. A treatment which addresses an early dysfunction might delay onset or even prevent the disease from developing, but be ineffective for those in later stages of the disease when the affected cells are being overwhelmed by other problems. A clinical trial with people in mid stage wouldn't be an appropriate test of this kind of treatment. We need to know more about what happens with the disease both before and after onset.

With the Predict HD study, researchers have made important advances along the strategic plan. It should be noted that more time is needed. The article reports on the first seventeen months of the study. It is not a true longitudinal study as yet. Most research participants weren't followed until their actual onset since most had not reached that point. Instead the time from onset was estimated based on CAG count using a formula developed in a recent study of 2913 individuals (Langbehn 2004) and participants were compared to one another based on motor assessment.

After experienced raters completed the Motor Assessment part of the UHDRS (United Huntington's Disease Research Scale), they recorded their answers to the question, "To what degree are you confident that this participant meets the operational definition of the unequivocal presence of an otherwise unexplained extrapyramidal movement disorder in a participant at risk for HD?" This yielded four comparison groups based on diagnostic confidence levels: no signs, soft signs, possible HD, and probable HD.

The researchers found high correlations among diagnostic confidence levels, motor scores, volume of the striatum in the brain, and probability of diagnosis in the next five years. Motor abnormalities were greater and striatal volume was decreased in those thought to be closer to diagnosis. Cognitive and psychiatric problems increased with diagnostic confidence levels.

These findings provide scientific support for what HD families have been saying all along: that symptoms do occur before major movement abnormalities. People with the HD gene and their families who are seeking assistance with disability insurance as well as support, counseling and medication for psychological symptoms and distress will be able to cite the Predict-HD study for validation.

The results so far have also been helpful in identifying potential biomarkers and clinical measures that will facilitate shorter and/or smaller clinical trials and eventually presymptomatic treatment. As more longitudinal data emerges from this study and the upcoming COHORT study, the best measures of preclinical and disease progression will be identified. More work needs to be and is being done, but a major start has been made.

On behalf of the entire Lighthouse community, I want to thank the HD warriors who volunteered their time to participate in this important study.

References

Langbehn DR, Brinkman R, Faulush D, Paulsen JS, Hayden MR. A new model for prediction of the age of onset and penetrance for Huntington's Disease based on CAG length. Clinical Genetics 2004;65:267-277.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 10 Jul 2006

Objective: To examine measures that may be associated with disease in the largest cohort ever recruited of prediagnosed individuals carrying the gene expansion for Huntington disease (HD).

Design: The Predict-HD study is a multicenter observational research study in progress at 17 sites in the United States, 4 in Canada, and 3 in Australia.

Setting: Genetics and HD outpatient clinics.

Participants: Five hundred five at-risk individuals who had previously undergone elective DNA analyses for the CAG expansion in the HD gene (predictive testing) and did not currently have a clinical diagnosis of HD.

Main Outcome Measures: Basal ganglia volumes on magnetic resonance images, estimated probability of diagnosis (based on CAG repeat length), performances on 21 standardized cognitive tasks, total scores on 3 scales of psychiatric distress, and motor diagnosis based on the Unified Huntington's Disease Rating Scale.

Results: Several variables showed progressive decline as the diagnostic ratings advanced toward manifest disease. Estimated probability of diagnosis was associated with Unified Huntington's Disease Rating Scale prediagnostic stages and varied from 15% in persons with no motor abnormalities to nearly 40% in those with abnormalities suggestive of probable disease. Striatal volumes, cognitive performances, and even psychiatric ratings declined significantly with motor manifestations of disease.

Conclusions: The documentation of biological and refined clinical markers suggests several clinical end points for preventive clinical trials. Longitudinal study is critical to further validate possible markers for prediagnosed HD.

Source: Archives of Neurology 2006 Jun;63(6):883-90.

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