Dr. LaVonne Veatch Goodman explains what endpoints are in clinical trials and why different endpoints are used in different HD drug trials.

What are endpoints?

Endpoints are specific measures chosen by researchers and drug companies to determine effectiveness of a drug in clinical trials. In phase III trials performed for FDA approval, endpoints are used to determine labeling of the drug when it is approved for sale. There are several different endpoint measures that have been used in Huntington's clinical trials. Change in UHDRS functional capacity (TFC) was the primary outcome measure in CARE, the first coenzyme Q-10 trial. Change in UHDRS chorea score was the outcome measure for recent tetrabenazine trials. Change in UHDRS total motor score is the outcome measure in Miraxion trials.

Why Different Clinical Trial Endpoints?

Although it is everyone's ultimate goal to get helpful drugs to HD patients, clinical trial sponsors choose endpoints that will meet the goals and answer the questions most important to the sponsor.

Successful drug companies choose clinical trial endpoints that will most quickly accomplish FDA approval of their drug. As example, the endpoint in Amarin's present Miraxion trial is change in total motor score over 6 months comparing drug to placebo in a pre-selected population of HD people with fewer than 44 CAG repeats. Using data from an earlier trial, this endpoint was explicitly designed to maximize chances for most efficient drug approval.

Academic scientists design trials that are more like laboratory experiments with the combined goals of answering scientific questions and testing drug response. This kind of trial is more complicated and has endpoints that describe drug response over the broader spectrum (motor, cognitive, psychiatric, and functional capacity) of disease. Scientists study mechanism of drug action, and try to correlate drug effects with radiographic, blood, urine or other study markers. This type of trial takes much more time: The first coenzyme Q-10 trial was 2.5 years long, and the upcoming second trial is planned to be as long as 5 years.

Which endpoints are best for HD People?

There is no perfect answer to this hard question because valid arguments can be made for both. It depends on perspective.

Pragmatically speaking, if you are a person with HD and your personal survival is important, you are likely to be more interested in trials that get drugs to you more quickly and won't put you at risk for long time periods of placebo. If you are a community physician, you'd like to be able to prescribe medicines to help HD patients as early as possible no matter what part of the disease it treats.

Scientifically speaking, if you are motivated to gain greater knowledge of disease and mechanism of drug response, you are more likely to be interested in more fastidious academic drug trials. This type of trial may (or may not) point the way for advancing future treatments, for instance if the perfect biomarker were found. But it will also delay drug approval and put patients at risk for longer time periods of placebo.

What do you think? Which kind of trial would you rather volunteer for? A short one geared to timely drug approval, or a longer one that may answer more scientific questions? Would your decision be the same if you knew you would receive placebo?

References

Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease. Neurology. 2001 Aug 14;57(3):397-404. PubMed abstract

Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology. 2006 Feb 14;66(3):366-72. PubMed abstract

Puri BK, Leavitt BR, Hayden MR, Ross CA, Rosenblatt A, Greenamyre JT, Hersch S, Vaddadi KS, Sword A, Horrobin DF, Manku M, Murck H. Ethyl-EPA in Huntington disease: a double-blind, randomized, placebo-controlled trial. Neurology. 2005 Jul 26;65(2):286-92. PubMed abstract