Galantamine Proves Its Worth in Yearlong Trial

Galantamine—The Enemy of Dementia

Galantamine Proves Its
Worth in Yearlong Trial

How would you conduct a long-term clinical trial on galantamine?
By Will Block

olding the power of life or death over other human beings, as physicians do, is the most awesome of responsibilities. It is sometimes shared by medical research scientists—for example, when they are investigating the efficacy of some pharmaceutical agent or nutritional supplement that shows promise for the treatment of a serious, progressive, incurable, and ultimately fatal disease, such as Alzheimer’s.

So that you can better appreciate the science behind the latest results regarding the benefits of galantamine in combating dementia, imagine that you are a medical researcher who seeks to undertake a long-term clinical trial of galantamine’s efficacy. How would you approach this task?

You Face Problems Galore

You’re faced with daunting problems, of which securing adequate funding is the first. Once the money is in the bag, you must address a host of scientific, technical, logistical, and administrative challenges (all of which, of course, had to be described in the funding proposal) in order to get the trial up and running. It’s a complex and demanding task involving many people (perhaps in different research groups scattered across the globe), with countless pitfalls that could undermine or even invalidate your efforts. You’d better know what you’re doing! (Well, we’re talking about you here, so of course you know what you’re doing.)

In addition to the problems mentioned above, there is a serious ethical problem you will have to address, because you’re dealing with human health and disease, and possibly life and death. You’ll see shortly what that problem is.

You Must Control the Power of the Mind

For the trial to have scientific validity, it must be conducted according to the highest possible standards—or the gold standard, as it’s often called. That means, among other things, that it must be placebo-controlled: the patients must be divided into two groups, one receiving the treatment in question (the treatment group) and the other receiving a dummy pill, or placebo (the control group). That way, when the results are analyzed, the notorious and often amazingly strong placebo effect can be factored out, leaving you with a clearer picture of the treatment’s actual efficacy.*


*If you want a perfect example of the power of mind over matter, look no further than the placebo effect (responding positively to something of no value because you think it should work for you and you very much want it to). It typically produces positive responses in about one-third of the patients involved in a clinical trial, and sometimes twice that many.


You Must Leave One Thing to Chance

You must carefully select the patients to be involved in the study, using criteria that will help you screen out anyone with characteristics (such as certain other medical conditions, or the taking of certain drugs) that might confound the results. Having done that, you must allocate the patients to the treatment (galantamine) and control (placebo) groups in a fully randomized manner, i.e., using some method of pure chance to decide who goes into which group. This is vital, lest your bias toward a favorable outcome for galantamine cause you to steer the patients you think are most likely to be helped by it into the treatment group, leaving the others for the control group—which would obviously invalidate the whole trial.

Now, please don’t take that remark personally. Everyone is susceptible to bias, whether conscious or unconscious, and everyone in medical research agrees that randomization is essential to help prevent it from tainting the results.

You Must Make Everyone Blind

Everyone also agrees that, to prevent another aspect of bias from creeping into the results, the protocol must be double-blind (except when this is impossible for practical reasons), meaning that neither you (and your staff) nor the patients know who is receiving what while the trial is underway. When it’s complete and the data have been compiled, then you may know who got what, and analyze the data. Blinding is accomplished by making the galantamine and the placebo (whether as tablets, capsules, or whatever) look, smell, feel, and taste identical so that you can’t tell them apart, and by coding them so that no one knows what they are except the keeper of the code, who is a person not involved in conducting the trial or compiling the data.

You Will Not Sleep Easy

Now we come to the ethical problem mentioned above—and by now, you’ve probably figured out what it is. You’re giving half the patients a treatment, galantamine, that is expected to help combat their Alzheimer’s disease—and that’s great. But you’re giving the other half nothing of value—just the hope (dampened by the fear that it will not be realized) that they’re in the treatment group, not the control group. (Of course, the treatment group has exactly the same hope and fear, but in their case, the hope is realized.)

In other words, you know that half the patients are receiving no real benefit from this trial, so their disease will get worse, and their lives may be shortened as a result. Your only solace is that the allocation of patients to the two groups was left to chance by the randomization process, and that all the patients and their legal caretakers understood this process and agreed in advance to participate in it. Still . . . .

How Much Are Patients’ Lives Worth?

The situation is bad enough—although necessary for the sake of scientific objectivity—but now comes another question: How long can you allow this to go on? Alzheimer’s is a long, slow process, and it takes time to evaluate the efficacy of anything that might retard its progress, let alone reverse it, if that’s even possible. A few weeks certainly won’t do it. A few months may show some significant results, but a year or more would surely be better.

But are you willing to let the control group continue to deteriorate for a year or more when you know (or at least have good reason to believe) that you could be helping them instead, by giving them galantamine? Are they willing? How much are their lives worth?

Wanted: Solomonic Wisdom

Those are tough questions. For better or worse, the answer to how long such a placebo-controlled trial can go on is 6 months. That’s the consensus of bioethicists, whose job it is to wrestle with agonizing problems such as these and try to come up with answers worthy of King Solomon. After 6 months, they’ve said, all bets are off: the data are what they are, and you must make the best you can of them. That does not necessarily mean, however, that the trial stops then and there.

What you can do—assuming the money is holding out and the patients are willing—is continue the trial, but on an open-label basis in which everyone gets galantamine, and knows it. The benefits to both groups are obvious: one gets to continue the treatment, the other gets to start it, albeit 6 months late. The downside, of course, is that now the placebo effect can no longer be factored out of the results, and that will cloud their interpretation. Still, it’s worth it. (For news on a non-placebo-controlled study, see the sidebar “Four-Year Benefit Found for Galantamine.”)

Four-Year Benefit Found for Galantamine

This just in: The results of a 4-year study of galantamine in Alzheimer’s disease have been announced at the 7th EFNS Congress (European Federation of Neurological Societies) in Helsinki.1 In the largest long-term study of its kind, researchers gave 240 patients 24 mg of galantamine daily for 48 months. The patients were tested periodically for cognitive performance (memory, learning ability, etc.) to assess the progress—or, more to the point, the slowing of the progress—of their disease.

Note that this was not a randomized, placebo-controlled, double-blind study. The patients’ decline in cognitive performance was simply compared with the known course of Alzheimer’s disease in untreated individuals. After 4 years, the results showed that the galantamine-treated patients’ cognitive functions deteriorated by an average of only 12.8 points on a standardized test, versus the expected decline of 26 to 32 points in untreated cases. Thus, it can be said that their expected cognitive deficit was reduced by at least 50%.

The study was conducted by Janssen-Cilag, a Johnson & Johnson subsidiary that manufactures galantamine for pharmaceutical use under the trade name Reminyl®. The study’s lead investigator said, “Patients treated continuously with Reminyl gained 12 to 18 months’ preservation of their cognitive function, significantly postponing their loss of independence, while reducing the burden on caregivers.”

  1. NewsRx bulletin (www.NewsRx.net), September 29, 2003.

The Ten-Country Study

The scenario described above was carried out recently by research groups in ten countries, under the coordination of scientists from Finland, Germany, Canada, the United Kingdom, and the United States.1,2 The agent being investigated was indeed galantamine, but not all the patients had Alzheimer’s disease: some had vascular dementia, which is the second most common type of dementia. With most galantamine research having been so strongly focused on Alzheimer’s disease, or AD, the researchers wanted to broaden the scope of inquiry to include vascular dementia, or VaD (for more information, see the sidebar "A Tale of Two Dementias").

A Tale of Two Dementias

The origins of Alzheimer’s disease (AD) are still largely a mystery, which makes prevention difficult; those of vascular dementia (VaD) are not, however. VaD is the result of cerebrovascular disease, which is essentially the same as cardiovascular disease, only it affects the brain instead of the heart. The primary causes are atherosclerosis and hypertension. Thus cerebrovascular disease—and, therefore, VaD—is as easy to prevent, through diet, exercise, and nutritional supplements, as is cardiovascular disease.

To complicate matters, however, it turns out that cerebrovascular disease is a risk factor not only for VaD, but also for AD. Another complication is that AD and VaD are often difficult to distinguish from each other. For one thing, the outward symptoms of dementia are essentially the same in both diseases. And even though the diseases have largely different origins and follow somewhat different courses of progression (mental decline in AD is steady, whereas in VaD it tends to be sporadic), they nonetheless have some commonalities in their causative factors and in the resultant damage to the brain—which is cumulative in both cases.

And, of course, it’s always possible that a patient may have both diseases, to one extent or another, which makes diagnosis that much more difficult. It is in your deepest interest to do whatever you possibly can to avoid them both.

For the study in question, the researchers enrolled patients in two categories: (1) AD with cerebrovascular disease (CVD) and (2) probable VaD. There were 592 patients (men and women, average age 75). In the galantamine group (396 individuals), 48% had AD with CVD, 43% had probable VaD, and 9% had an intermediate diagnosis (dementia, but unspecified). In the control group (196 individuals), these percentages were almost identical. In both groups, about two-thirds had cardiovascular disorders, which is hardly surprising, considering the patients’ poor state of cerebrovascular health.

Phase I: Double-Blind

Phase I of the trial—randomized, placebo-controlled, and double-blind—lasted 6 months.1 Galantamine or placebo was administered orally, twice daily, following a dose-escalation schedule that culminated in a daily dose of 24 mg after the first 6 weeks (galantamine is best taken in small amounts at first, building up slowly to the full amount). The patients were evaluated several times, using a number of internationally accepted, standardized test protocols, on measures of cognition, functional ability in daily life, and behavioral symptoms.

Not surprisingly, the control patients did poorly: their condition continued to deteriorate in accord with expectations for their respective types of dementia. By contrast, the galantamine-treated patients showed significant improvements in both types of dementia, relative to the baseline values measured at the outset of the study, i.e., they gained ground. The improvements noted were similar in magnitude to those seen previously in gold-standard galantamine studies on patients with Alzheimer’s disease.3,4,5


The galantamine-treated patients
showed significant improvements
in both types of dementia, i.e.,
they gained ground. This is
particularly gratifying, because
with conventional anti-Alzheimer’s
drugs, the best one can usually
hope for is to stop losing ground.


Such improvement in the treatment group is particularly gratifying, because with conventional anti-Alzheimer’s drug therapy, the best one can usually hope for is to stop losing ground, i.e., to hold steady, for about 6 months, after which the drugs start to lose their effectiveness, and the mental deterioration resumes.

Phase II: Open-Label

In Phase II of the trial—the open-label, 6-month extension of Phase I—all the patients were eligible to continue, and 459 of them (78%) did, receiving 24 mg/day of galantamine.2 As in Phase I, both groups were put through a 6-week dose-escalation regimen to 24 mg/day. For the original control group (which needed this), the regimen was genuine, but for the original treatment group (which did not), it was a sham, the purpose of which was to prevent anyone from knowing which group they had been in during Phase I. Thus the patient-blinding in this study was preserved.

The results of Phase II were positive overall. Although the original treatment group did not show continued improvement, they largely maintained the gains made during Phase I, which in itself is a significant achievement in the treatment of dementia. And the original control group showed marked improvement in cognition and behavior (but not functional ability), largely regaining the ground they lost during Phase I. In the authors’ words:

The results of this study suggest that galantamine has long-term effectiveness in patients with VaD and AD with CVD. Cognitive function and behavior were maintained for 12 months with galantamine 24 mg/d, and significant benefits were seen in terms of functional ability. . . . In addition, after 6 months of open-label galantamine treatment, patients who had been randomized to receive placebo in the double-blind phase showed improvement or no deterioration in cognition from baseline.

Prevention Is the Key

Thus, the effort to extend the original 6-month trial (the usual duration of such trials) by another 6 months was surely worth it, because it gave additional emphasis to the apparent therapeutic superiority of galantamine over other Alzheimer’s treatments, which typically do not show such benefits for more than about 6 months. This also lends further support to the credibility of galantamine as a probable preventive agent for Alzheimer’s disease—and prevention is surely incomparably more desirable than treatment.

References

  1. Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV. Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet 2002 Apr 13;359:1283-90.
  2. Erkinjuntti T, Kurz A, Small GW, Bullock R, Lilienfeld S, Damaraju CV. An open-label extension trial of galantamine in patients with probable vascular dementia and mixed dementia. Clin Ther 2003;25(6):1765-82.
  3. Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in Alzheimer’s disease. Neurology 2000;54:2269-76.
  4. Raskind MA, Peskind ER, Wessel T, Yuan W, and the Galantamine USA-1 Study Group. Galantamine in AD: a 6-month, randomized, placebo-controlled trial with a 6-month extension. Neurology 2000;54:2261-8.
  5. Wilcock GK, Lilienfeld S, Gaens E, on behalf of the Galantamine International-1 Study Group. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: a multicentre randomised controlled trial. Brit Med J 2000;321:1445-8.

Dual-Action Galantamine

Galantamine provides a heralded dual-mode action for boosting cholinergic function: it inhibits the enzyme acetylcholinesterase, thereby boosting brain levels of acetylcholine, and it modulates the brain's nicotinic receptors so as to maintain their function. The recommended daily serving ranges from a low of 4 to 8 mg of galantamine to begin with to a maximum of 24 mg, depending on the individual's response.

For an added measure of benefit, it is a good idea to take choline, the precursor molecule to acetylcholine, as well as pantothenic acid (vitamin B5), an important cofactor for choline. Thus it is possible to cover all bases in providing the means to enhance the levels and effectiveness of your acetylcholine.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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