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[00:00:42] Dr. Rob de Bie: Thank you very much, Sara.
[00:00:44] Dr. Sara Schaefer: So first, could you please review briefly the initial LEAP study and its results?
[00:00:51] Dr. Rob de Bie: So, the initial LEAP trial was set up to investigate whether levodopa has a disease modifying effect. And to distinguish between a [00:01:00] direct symptomatic effect and a disease modifying effect, we used to randomize the late start design. And in this study, 445 patients with early PD, who not yet used any medication, were randomized into two groups.
So one group of patients received levodopa, 100 mg three times a day, for 80 weeks. And the other group first received the placebo three times a day, for 80 weeks. for 40 weeks, which was followed by levodopa, 100 mg, 3 times a day for the next 40 weeks. Thus, both groups were followed for 80 weeks. And if at the end of the 80 weeks, there was a difference in severity of symptoms between the two groups, this difference would be due to the difference in treatment during the first 40 weeks, as one group received levodopa and the other received placebo.
And this effect would have persisted throughout the second 40 weeks. The outcome of the LEAP trial was that [00:02:00] at the end of the 80 weeks, there was no difference in the severity of Parkinson's symptoms between the two groups. And this outcome supports the hypothesis that levodopa does not have a disease modifying effect.
[00:02:12] Dr. Sara Schaefer: And so this was an extension study of that trial that went on for five total years of follow up for these patients. What was the rationale for the extension study?
[00:02:28] Dr. Rob de Bie: So we measured the severity of the disease with the UPRS. And in the LEAP trial, All patients used levodopa during the second 40 weeks. So at the end of the 80 weeks, the UPDRS score was almost the same as a baseline. It is possible that the use of levodopa and its symptomatic effect masked any potential difference in disease progression between the two groups. We could have chosen to measure the patients during a standardized off phase, [00:03:00] but so early in the disease, there is no guarantee that the effect would have worn off after 12 or 24 hours. And this procedure would also likely have a negative effect at the retention rate. And we also did not have the financial resources for this. if levodopa indeed has no disease modifying effect, then there should also be no difference between the two groups after five years. So with additional funding, we were able to test this hypothesis. An advantage of this was that we could verify the diagnosis of Parkinson's disease after five years and thus repeat the analysis with patients whose disease was more certain.
[00:03:46] Dr. Sara Schaefer: Yeah. In those early patients, you definitely need to be cautious about that long dose effect, which we've covered in this podcast and in previous episodes. How did you ultimately conduct the follow up?
[00:03:58] Dr. Rob de Bie: So after three [00:04:00] and five years, we remeasured the severity of the disease using the UPDRS and the use of antiparkinsonian medication. In addition to these comparisons, we also grouped UPDRS items into levodopa responsive and less levodopa responsive symptoms. Unfortunately, we only received sponsorship for the follow up study after some of the patients had already passed the three year mark. This does not introduce bias, but it does result in slightly less statistical power at the three year point. The five year mark is the most important measurement point in this study, though.
[00:04:35] Dr. Sara Schaefer: And what did you find?
[00:04:37] Dr. Rob de Bie: So, after three and five years, there was also no difference in disease severity, progression, motor fluctuations, and no difference in the amount of medication use. So, this finding supports the idea that levodopa does not influence disease progression.
[00:04:53] Dr. Sara Schaefer: I found it interesting that there was not only no difference in UPDRS scores or markers of [00:05:00] progression, but that there was also no difference in motor fluctuations, which. As I'm sure you know is a big debate about how much levodopa and early start levodopa might contribute to that. .
So the LEAP study ultimately set out to determine if levodopa affects disease course. Do you think at this point we've answered the question?
[00:05:23] Dr. Rob de Bie: I actually think we have. If levodopa does have any effect on disease progression, it is very small and negligible compared to its symptomatic effect.
[00:05:33] Dr. Sara Schaefer: What are the take home points for providers who treat Parkinson's patients in your view?
[00:05:40] Dr. Rob de Bie: So, the main message is that you can tell now patients that it has been proven that levodopa does not affect disease progression. This is different from saying it has not been proven that levodopa accelerates disease progression. You can start with Levodopa if needed, and if you're [00:06:00] unsure about the right time to start, it does not matter if you start a little earlier. However, this is not a license to use it unnecessarily or at too high dose. There is also no positive long term effect of early levodopa use, so people early in the disease with no or few functional limitations can still participate in scientific research that requires delaying the start of levodopa.
[00:06:26] Dr. Sara Schaefer: Sounds good. So basically use your clinical judgment.
[00:06:30] Dr. Rob de Bie: Yes.
[00:06:32] Dr. Sara Schaefer: All right. Well, thank you very much for joining us today and for telling us about your study and what conclusions you drew.
[00:06:39] Dr. Rob de Bie: Thank you very much