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ABC: Are you and/or your colleagues
disappointed in the outcome? Had you expected a positive result?
Dr. DeKosky: Of course we were
disappointed not to be able to identify an intervention that would slow or
delay the development of Alzheimer's disease or all-cause dementia. I don't
think I would characterize my view as “expecting a positive result.” That's why
we do double-blind studies that are placebo controlled—to keep our
expectations/hopes out of the objective evaluations. We've learned from many
studies that just because a drug or compound has a particular biochemical
action that has logic as a possible therapy does not mean that it will work in
a double-blind clinical trial. Lots of failed drugs or substances have taught
us that, along with the usual caveats about dose levels, frequency of dosing,
duration of treatment, appropriate outcomes, etc.
ABC: Is there any issue you wish to
discuss regarding the 60% compliance at completion? Some have raised a question
as to whether this relatively low compliance toward the end of the trial might
discount the significance of the trial’s conclusions.
Dr. DeKosky: Mean follow-up was 6.1
years and treatment adherence was 70% over that period. This level of treatment
adherence in GEMS is comparable to other large trials in significantly younger
populations. For example, in ALLHAT, at 5 years, 80% of patients were on the
assigned diuretic but only 63% were on a diuretic and not on one of the other
treatments being tested. Plus, the mean age of this population at outset was
67. In the SHEP study, 44% of the people in the placebo arm were on one of the
antihypertensive agents being tested at the end of the 5 year trial. The are
many other examples that demonstrate that GEMS treatment adherence was
outstanding for a clinical trial and a true reflection of what clinical
practice, where all trials should be applied, would be.
From
our statistician: “I agree and would add that a major reason for ‘lack of
adherence’ is that the person either died, became demented, or was suffering
from illnesses that make adherence difficult or impossible. In a trial of
people over 75, the level of adherence is remarkable and almost certainly is
better than would be experienced in a non-trial everyday life situation.”
ABC: In your paper you mentioned that a
longer duration might have resulted in a different trend. Any estimate on how
much longer might have been reasonable to expect such, i.e., if that were
possible?
Dr. DeKosky: We know from OBSERVATIONAL
(e.g., epidemiological) studies that there are associations of health
activities and medication taking in midlife that relate to diseases in late
life. It is theoretically possible that if you start people on medications in
midlife that they may have effects in late life. There is no way to know how
long that should be. Obviously a trial that lasts several decades has
logistical issues, including adherence, money, NIH prioritizing of studies,
etc. So while it is easy for me or anyone to toss off a line that “perhaps if
we started people taking ginkgo at age 40 it would have an effect at 80” it is
important to keep in mind that we have no data to say that that is correct. I
understand that is what a number of people have said, in response to our
negative study in late life. It's important to keep in mind that it is easy to
say that without data. I can only comment on what we have data for. In
addition, the question the NIH asked us to address was whether we could give
ginkgo extract to people in late life and delay onset of disease.
ABC: Some say this trial is definitive,
i.e., proving that the ginkgo extract used is not effective for preventing
dementia and AD in either cognitively intact or impaired older adults. Yet the
French GuidAge ginkgo prevention trial (Andrieu et al) has not yet been
completed. Any comments?
Dr. DeKosky: Well, the GuidAge study
had a slightly different design, and of course we will see what it shows. I
think we would have felt more positive if we had seen any sort of hint of an
emerging positive effect in our study. The GuidAge study also looked at people
in late life.
ABC: What do you think about the evidence
showing benefit for EGb 761 for treatment of dementia and AD, e.g., positive
trials by Lebars et al (1997), Napryeyenko et al (2007), Ihls et al (abstract
at Alzheimer's Congress in Chicago in July 2008), and other trials,
particularly those comparing ginkgo favorably with cholinesterase inhibitors
(e.g., ginkgo vs. donepezil in Mazza et al, 2006).
Dr. DeKosky: I think there is little
evidence that Gingko is remarkably effective in AD (I participated in the
design and carrying out of a large double blind, placebo controlled negative
study (Schneider et al, 2005). There is variability in the quality, size, and
outcome of studies in AD. The Lebars study was not a positive study since, if I
remember, it did not hit all of its outcomes and had very large dropout (50% I
think) and very slow change in both the placebo and treatment group. I think
the message of these studies is that if it has an effect in symptomatic AD it
is not a very powerful one.* The meta-analyses for the esterase inhibitors (not
that they are as powerful as we would like medications to be) show a much more
consistent effect. However, our study's data do not address that issue since
anyone with dementia at screening was excluded from the study.
ABC: What about the evidence suggesting
the potential benefits of GBE in normal healthy adults for improved cognitive
activity for daily tasks, i.e., aside from results of the trial by Solomon et
al in JAMA (2002), e.g., the Crews et al (2005) review of 16 RCTs in HerbalGram?
Dr. DeKosky: Again, my data don't
address these studies, so I don't have a comment on these. If you do want an
expert commentary on the overview reviews, I suggest you contact Lon Schneider
at USC, who wrote the editorial for our paper in JAMA and is an expert on these
issues.
ABC: Any other comments?
Dr. DeKosky: I recognize that your
organization's raison d'etre is to be supportive of botanical products use. I
and my colleagues did not approach this study with anything but a neutral
researchers view and I would have been happy had we shown an effect.
*ABC
Editor’s note: ABC respectfully raises
its disagreement with Dr. DeKosky on both the outcome of the LeBars trial in
JAMA in 1997 and the matter of the value of esterase inhibitors in the
treatment of dementia. With respect to the LeBars trial,3 there were
statistically significant improvements in both the ADAS-Cog (Alzheimer’s
Disease Assessment Scale-Cognitive Subset, the “gold standard” in measurement
of memory in Alzheimer’s patients) and the GERRI (Geriatric
Evaluation of Relative's Rating Instrument , a survey of family-member
caregivers) scores. In addition, several studies suggest only marginal effects
of esterase inhibitor and related prescription drugs, e.g., per the recent
article by Rebecca Voelker in the Journal
of the American Medical Association.4
References
1. DeKosky ST, Williamson J, Fitzpatrick A, et al for the
GEM Study Investigators. Ginkgo biloba for primary prevention of dementia:
Results of the Ginkgo Evaluation of Memory (GEM) Study. JAMA. November
19, 2008;300(19):2253-2262.
2. Ginkgo's Benefits for Treatment of Symptoms of Cognitive
Decline and Other Uses Are Supported by Scientific Research. HerbalEGram. November
2008;5(11).
3.
LeBars EL, Katz MM, Berman N, Turan M, Freedman AM, Schatzberg AF. A
placebo-controlled, double-blind, randomized trial of an extract of Ginkgo
biloba for dementia. JAMA.
1997;278:1327-1332.
4.
Voelker R. Guideline: Dementia drugs’ benefit uncertain. JAMA. April 16, 2008;299(15):1763.
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