Who would believe that galantamine could be so effective?

Galantamine Benefits
Alzheimer’s for 48 Months

A big leap for efficacy has been reported in a
randomized, double-blind, placebo-controlled withdrawal trial
By Will Block

I n a new study just published online, the natural alkaloid galantamine was found to continue improving symptoms in Alzheimer’s disease (AD) patients far longer than anyone suspected.1 Researchers at several Italian Universities and affiliated hospitals set out to examine long-term outcomes of continuing galantamine treatment beyond 12 months, up until which there had been no further cognitive deterioration.

There were two phases to the study. Phase one was an open label and lasted 12 months. This was followed by a double-blind, randomized, placebo-controlled withdrawal phase lasting up to 24 additional months. All subjects had been previously diagnosed with mild to moderate AD; they were given up to 16 mg/day of galantamine.


Galantamine was effective in delaying
time to cognitive deterioration in
subjects with mild to moderate AD.


The subjects were eligible for the double-blind phase if they did not decline 4 points or more on the AD Assessment Scale-cognitive subscale (ADAS-cog/11)* by the end of the open label phase (month 24, given the prerequisite phase of 12 months). The differences between galantamine and placebo in length of time to dropout were estimated using the Cox proportional hazard model (a class of survival models in statistics). Almost 1/2 of the galantamine group (47.4%) completed the double blind phase, while less than 1/3 (31.7%) of the placebo subjects did. The reason for discontinuing placebo prematurely, compared with galantamine subjects, was attributed to either lack of efficacy or some other reason; no statistically significant difference was seen for a change in ADAS-cog ≥4 between treatment groups. Subjects who responded to 12 months of galantamine treatment benefited from continued drug therapy for up to 36 months. That’s 48 months in total. Galantamine was effective in delaying time to cognitive deterioration in subjects with mild to moderate AD. Treatment was generally safe and well tolerated.


*ADAS-cog/11 consists of 11 tasks measuring the disturbances of memory, language, praxis (motor coordination), attention, and other cognitive abilities which are often referred to as the core symptoms of AD.

†The total score of ADAS-cog ranges from 0 to 70, higher scores mean greater cognitive impairment such as poorer recall and recognition memory.


Confirming the Significant Effect of Galantamine

A systematic review of galantamine in AD and mild cognitive impairment, including 10 randomized, placebo controlled trials with a duration of longer than 10 weeks and a total of 6805 subjects, confirmed a significant treatment effect of galantamine over placebo with regards to cognition, activities of daily living, and behavioral symptoms at doses between 16 to 24 mg per day.2

In a study published two years earlier, results from long-term open label extension trials suggest that a sub-group of AD patients treated with galantamine remained stable in the cognitive domain for up to 14 months3 and that a third of treated patients showed very slow symptom progression up to 48 months.4 However, most well controlled clinical trials present treatment outcomes at 5 to 6 months. Therefore they are limited in the information that can be provided about long-term effects in a chronic disease such as AD. In addition, healthcare decision makers have acknowledged the beneficial outcomes of galantamine but raised doubts about long term effectiveness.5

Going Beyond One Year

Returning to the current study, in order to examine long-term outcomes in more depth, a clinical trial was conducted to assess whether continuing treatment with galantamine for up to 24 months might result in delaying the cognitive deterioration associated with AD, compared with cessation of treatment after 12 months. When the study was designed, there were no placebo-controlled, long-term studies available to demonstrate efficacy, safety, and tolerability of galantamine over one year of treatment.

Altogether, this multicenter study was conducted at 29 study sites in Italy between July 2001 and November 2005. Subjects were eligible to participate if they were out patients (living outside a medical facility), aged ≥50 years, and had received a diagnosis of probable AD according to the National Institute of Neurologic and Communicative Disorders and Stroke and AD and Related Disorders Association (NINCDS-ADRDA), with mild to moderate cognitive impairment [with a Mini Mental State Examination (MMSE) score from 11 to 24]. Subjects were excluded if: 1) a neurodegenerative disorder other than AD was present, 2) there was any serious and clinically significant illness, 3) if there was a history of previous cerebral infarction, or 4) acetylcholinesterase inhibitors were used within 3 months before inclusion.


For each year of treatment with
galantamine, the risk of ending up in
a nursing home was reduced by 31%.


Subjects were required to withdraw from the study if they showed a cognitive deterioration (≥4 points of the ADAS-cog/11 score) at the end of the open label phase or at any time during the double blind phase. Other reasons for withdrawal included dropping of consent by either the caregiver or the patient, or if the randomization code was broken. Withdrawal could also occur if a serious adverse event occurred or if the investigator thought it to be in the best interest of the patient.

Cholinomimetics, anti-depressants, and mood stabilizers were not allowed during the trial. Neither were other antidementia agents (aside from galantamine) such as other cholinesterase inhibitors (donezepil, tacrine, rivastigmine) or nootropics.


The tolerability of galantamine
improved with the
duration of treatment.


Informed written consent for both patients and caretakers was required, and the trial conformed to guidelines on good clinical practice from the International Conference on Harmonization (ICH). This also consisted of technical requirements for registration of pharmaceuticals for human use. Moreover, the trial was approved by the local ethics committee of each of the centers.

Galantamine Treatment Subjects Went On

The results found that galantamine-treated subjects stayed on treatment longer than placebo treated subjects, and that galantamine was successful in maintaining patients on treatment for an additional 24 months, without a significant decline in cognitive deterioration, as defined in this study. As previously acknowledged, subjects treated with placebo were more likely to discontinue prematurely than subjects treated with galantamine. And as previously stated, there were no statistically significant differences in the likelihood of premature study discontinuation owing to a change in ADAS-cog/11 ≥4 (higher scores mean greater memory impairment) between treatment groups. The hazard ratio (HR) was similar for each group, showing consistency across analyses. HR is an explanatory variable of survival analysis concerning the hazard or risk of an event. In other words, HR involves an estimate of relative risk.

Survival Analysis Weakness

In the current study, deterioration of ADAS-cog/11 was based on only 27 subjects who dropped out when they exceeded ADAS-cog/11 ≥ 4. Consequently, the ADAS-cog analysis was underpowered. Confounding the results as well, 45 subjects withdrew before they reached a cognitive deterioration of ADAS cog/11 ≥ 4. Thus it was not possible to know if these subjects would have been eligible for the ADAS-cog/11 survival analysis. Hence, even though the recruitment target was met, the “other reason” drop-out numbers were higher than expected, altering the power of the study. Subjects with a higher MMSE score when the study began were more likely to respond to galantamine treatment and were less likely to show cognitive decline. Additionally, subjects who responded to treatment after 12 months benefited from continuing treatment with galantamine.


Treatment should be continued in
patients with AD who benefit from
galantamine therapy.


Yet, postponing cognitive deterioration can delay time to nursing home institutionalization as a recent study has found.6 In this study, the length of treatment with galantamine was associated with a reduced risk of being institutionalized; for each year of treatment with galantamine, the risk of ending up in a nursing home was reduced by 31%. This, along with the comparably lower expenses of informal caregivers should reduce associated healthcare costs.

Declining Health Mires Measurements of Cognition

It is a challenge to measure cognitive functions over prolonged periods of time in patients with AD because of the declining health of subjects, which leads to a large number of dropouts. The current study avoided this difficulty by using a withdrawal design and measuring time to dropout. This meant that there were no missing data. Yet, as propounded above, this study was not sufficiently powered for the ADAS-cog/11 survival analysis for the reasons worth repeating: many subjects dropped out before they reached a difference in ADAS-cog/11 ≥4 and only 27 subjects qualified by exclusion of this measured cognitive decline (difference in ADAS-cog/11 ≥4).

Thus, the withdrawal design could raise an ethical issue because some subjects who responded positively to galantamine were randomized to placebo treatment, and effective treatment was stopped. Opposing this was the lack of information in the literature at the time of trial planning, concerning the efficacy of galantamine in a long-term treatment perspective. In fact, every one of the local ethics committees of the clinical centers gave formal approval to the design, so important did they consider the undertaking.

The slotting of randomization could be an unusual design feature of the trial because it took place at the beginning of the open label phase, rather than the double-blind phase. Nevertheless, this does not seem to have negatively affected the study, and the subjects were still well balanced.

Of importance, neuropsychiatric and behavioral scales such as the Neuropsychiatric Inventory (NPI) and the Alzheimer’s Disease Cooperative Study group–Activities of Daily Living (ADCS-ADL) scale were not used in this study. It’s possible that they might have been useful to assess the functional status of the patients. But no design is ever perfect, and Monday morning-quarterbacking is guaranteed to find flaws.

Toleration, Safety, and Benefits

Data from this study have provided supporting evidence that galantamine is well tolerated when used for long term treatment, as has been shown in other studies.7–10 The tolerability of galantamine improved with the duration of treatment. Many of the adverse events seen in this study were typical of those encountered after administration of cholinesterase inhibitors. Regarding the safety profile of galantamine deducible from this study, there isn’t enough data for analysis to be made. Therefore, data from other studies should be considered for safety and tolerability of galantamine.

For example, a meta-analysis of mortality data from double-blind, placebo-controlled randomized trials and a recontact study to collect longer term mortality data found no evidence of increased risk of mortality associated with the use of galantamine in patients with AD.11 On the basis of the evidence from this study, and in line with current guide lines, treatment should be continued in patients with AD who benefit from galantamine therapy, and interruption of therapy in specific patients should be undertaken with caution. Treatment should only be discontinued if the patient experiences untoward effects.


Subjects who responded to 12 months
of galantamine treatment benefited
from continued therapy for
up to 36 months.


In summation, subjects who responded to 12 months of galantamine treatment benefited from continued therapy for up to 36 months. Galantamine effectively delayed the time to dropout due to any reason or for lack of efficacy in subjects with mild to moderate AD. Treatment was generally safe and well tolerated.

References

  1. Scarpini E, Bruno G, Zappalà G, Adami M, Richarz U, Gaudig M, Jacobs A, Schäuble B. Cessation versus Continuation of Galantamine Treatment after 12 Months of Therapy in Patients with Alzheimer’s Disease: A Randomized, Double Blind, Placebo Controlled Withdrawal Trial. J Alzheimers Dis 2011 May 23. [Epub ahead of print]
  2. Loy C, Schneider L, Galantamine for Alzheimer’s disease and mild cognitive impairment. Cochrane Database Syst Rev 2006 Jan 25;(1):CD001747.
  3. Lyketsos CG, Reichman WE, Kershaw P, Zhu Y. Long-term outcomes of galantamine treatment in patients with Alzheimer disease. Am J Geriatr Psychiatry 2004 Sep-Oct;12(5):473-82.
  4. Rockwood K, Dai D, Mitnitski A. Patterns of decline and evidence of subgroups in patients with Alzheimer’s disease taking galantamine for up to 48 months. Int J Geriatr Psychiatry 2008 Feb;23(2):207-14.
  5. Institute for Quality and Efficiency in HealthCare. Cholinesterase inhibitors in Alzheimer’s disease. https://www.iqwig.de/search.159.en.html. Updated April 4, 2007. Accessed June 25, 2011.
  6. Feldman HH, Pirttila T, Dartigues JF, Dartigues JF, Everitt B, Van Baelen B, Schwalen S, Kavanagh S. Treatment with galantamine and time to nursing home placement in Alzheimer’s disease patients with a and without cerebrovascular disease. Int J Geriatr Psychiatry 2009;24:479-88.
  7. Bullock R, Erkinjuntti T, Lilienfeld S, G GAL-INT-6 Study Group Management of patients with Alzheimer’s disease plus cerebrovascular disease: 12-month treatment with galantamine. Dement Geriatr Cogn Disord 2004;17:29-34.
  8. Erkinjuntti T, Kurz A, Small GW, Bullock R, Lilienfeld S, Damaraju CV, GAL-INT-6 Study Group. An open label extension trial of galantamine in patients with probable vascular dementia and mixed dementia. Clin Ther 2003;25:1765-82.
  9. Pirttil¨a T, Wilcock G, Truyen L, Damaraju CV. Long-term efficacy and safety of galantamine in patients with mild-to-moderate Alzheimer’s disease: multicenter trial. Eur J Neurol 2004;11:734-41.
  10. Feldman HH, Pirttila T, Dartigues JF, Everitt B, Van Baelen B, Brashear HR, Berlin JA, Battisti WP, Kavanagh S. Analyses of mortality risk in patients with dementia treated with galantamine. Acta Neurol Scand 2009;119:22-31.
  11. Caltagirone C, Bianchetti A, Di Luca M, Mecocci P, Padovani A, Pirfo E, Scapicchio P, Senin U, Trabucchi M, Mussico M. Guidelines for the treatment of Alzheimer’s disease from the Italian association of psychogeriatrics. Drugs Aging 2005;22(Suppl 1):1-26.


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

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