Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer’s disease

Abstract

Background

Currently available treatments for Alzheimer’s disease (AD) can produce mild improvements in cognitive function, behavior, and activities of daily living in patients, but their influence on long-term survival is not well established. This study was designed to assess patient survival and drug efficacy following a 2-year galantamine treatment in patients with mild to moderately severe AD.

Methods

In this multicenter, double-blind study, patients were randomized 1:1 to receive galantamine or placebo. One primary end point was safety; mortality was assessed. An independent Data Safety Monitoring Board monitored mortality for the total deaths reaching prespecified numbers, using a time-to-event method and a Cox-regression model. The primary efficacy end point was cognitive change from baseline to month 24, as measured by the Mini-Mental State Examination (MMSE) score, analyzed using intent-to-treat analysis with the ‘last observation carried forward’ approach, in an analysis of covariance model.

Results

In all, 1,024 galantamine- and 1,021 placebo-treated patients received study drug, with mean age ~73 years, and mean (standard deviation [SD]) baseline MMSE score of 19 (4.08). A total of 32% of patients (661/2,045) completed the study, 27% (554/2,045) withdrew, and 41% (830/2,045) did not complete the study and were discontinued due to a Data Safety Monitoring Board-recommended early study termination. The mortality rate was significantly lower in the galantamine group versus placebo (hazard ratio [HR] =0.58; 95% confidence interval [CI]: 0.37; 0.89) (P=0.011). Cognitive impairment, based on the mean (SD) change in MMSE scores from baseline to month 24, significantly worsened in the placebo (−2.14 [4.34]) compared with the galantamine group (−1.41 [4.05]) (P<0.001). Functional impairment, based on mean (SD) change in the Disability Assessment in Dementia score (secondary end point), at month 24 significantly worsened in the placebo (−10.81 [18.27]) versus the galantamine group (−8.16 [17.25]) (P=0.002). Incidences of treatment-emergent adverse events were 54.0% for the galantamine and 48.6% for the placebo group.

Conclusion

Long-term treatment with galantamine significantly reduced mortality and the decline in cognition and daily living activities, in mild to moderate AD patients.

Identification

This study is registered at ClinicalTrials.gov (NCT00679627).

Keywords:

• cholinesterase inhibitors
• cognition
• long-term treatment
• mortality
• nicotinic

View correction statement:

Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer’s disease [Corrigendum]

Supplementary material

Table S1 Demographic and baseline characteristics (completers analysis set)

Table S2 Medical history (safety analysis set)

Table S3 Medical history (completer analysis set)

Acknowledgments

We thank Dr Madhavi Patil (SIRO Clinpharm Pvt. Ltd.) for providing writing assistance and Dr Wendy P Battisti (Janssen Research and Development, LLC) for providing expert editorial assistance. The authors wish to thank Dr Walter Neto, formerly employed by Janssen Research and Development, LLC for his contribution as Project Physician in the early stages of the study. The authors thank the study participants, without whom this study would not have been accomplished, as well as the following investigators for their participation in this study:

Czech Republic: Bartova Petra, MD; Brunovsky Martin, MD, PhD; Cernohorsky Dusan, MD; Latalova Klara, MD; Pietrucha Slavomir, MD; Topinkova Eva, MD, PhD; and Vaclavik Daniel, MD. Estonia: Andresen Kadri, MD; Ennet Jüri, MD; Gross-paju Katrin, MD, PhD; Linnamagi Ulla, MD, PhD; Schults Marje, MD; and Talvik Pille, MD. France: Dantoine Thierry, PhD. Germany: Bittkau Simon, MD; Bodenschatz Ralf, MD; Böhringer Johannes, MD; Diery Hans D, MD; Dorn Brita, MD; Glatzel Dirk, MD; Hager Klaus, MD; Horn Rolf, MD; Hundt Wolfgang, MD; Hüntemann Reinhard, MD; Käfferlein Wolfgang, MD; Koppai-reiner Joachim, MD; Krug Reinhard, MD; Müller Friedemann, MD; Müller Thomas, MD; Niklewski Guenter, MD; Oldenburg Wolfgang, MD; Peltz Jörg, MD; Sallach Klaus MD; Schoell Irma, MD; Sigel Karl-Otto, MD; Springub Joachim, MD; Vollmuth Markus, MD; Wiswedel Henning, MD; and Zerr Inga, MD. Greece: Papanastasiou Ioannis, MD; Spinaki Cleanthe, MD, PhD; and Tsolaki Magda, MD, PhD. Italy: Barbanti Piero, MD; Lorusso Sebastiano, MD; Mazzei Bruno, MD; Onofrj Marco, MD; Postacchini Demetrio, MD; Scarpino Osvaldo, MD; and Stracciari Andrea, MD. Latvia: Sarkane Rudite, MD. Lithuania: Budrys Valmantas, MD and Liesiene Vanda, MD. Romania: Badescu Alexandra, PhD; Chirita Vasile, PhD; Dan Irina-Ana, PhD; Fodoreanu Liana, PhD; Gabos-Grecu Iosif, PhD; Giurgiuca Liana, PhD; Lapadat Mihaela, MD; Marinescu Victor, PhD; Pantu Camelia Mihaela, MD; Podea Delia, MD, PhD; Rosca Mihaela Cleopatra, MD; and Tudose Catalina, PhD. Russia: Agarkov Alexey, MD; Balunov Oleg, MD, PhD; Belova Anna, MD; Burdukovsky Mikhail, MD; Dobrovolskaya Natalya, MD; Gavrilova Svetlana, MD, PhD; Gribanov Andrey, MD; Gustov Alexander, MD; Ivlieva Irina, MD; Khasanova Dina, MD; Kolchev Alexander, MD, PhD; Lebedeva Anna, MD, PhD; Malakhova Anna, MD; Maslova Natalya, MD, PhD; Neznanov Nikolay, MD, PhD; Odinak Miroslav, MD, PhD; Pizova Natalya, MD, PhD; Sherman Mikhail, MD; Sheyfer Mikhail, MD, PhD; Shiryaev Oleg, MD; Sitchikhin Pavel, MD; Sluchevskaya Sofia, MD, PhD; Suchkov Yuri, MD; Tadtaev Vitaly, MD; Vacula Irina, MD; Vaulin Sergey, MD, PhD; Yakhin Kausar, MD, PhD; Zagoruyko Elena, MD; and Zayka Vladimir, MD, PhD. Slovakia: Dvorak Miloslav, MD, PhD; Janikova Eva, MD; Mateffy Izabela, MD; Milichovska Daniela, MD; Molcan Peter, MD; Perichtova Magda, MD; Sarissky Peter, MD; Turcani Peter, MD, PhD; Vavrusova Livia, MD, PhD; and Vavrusova Livia, MD, PhD. Slovenia: Flisar Dusan, MD, PhD; Pirtosek Zvezdan, MD, PhD; and Stare Lidija, MD. Ukraine: Abramov Volodymyr, MD, PhD; Bachinskaya Natalia, MD; Bitenskyy Valery, MD, PhD; Blazhevych Yulia, MD; Demchenko Vladislav, MD, PhD; Dubenko Andriy, MD, PhD; Kulyk Bohdan, MD, PhD; Kushnir Grygory, MD, PhD; Litvinenko Nataliya, MD, PhD; Lytovchenko Tetyana, MD, PhD; Maruta Natalia, MD, PhD; Maryenko Lidiya, MD, PhD; Moroz Olena, MD; Moroz Svitlana, MD, PhD; Palamarchuk Pavlo, MD; Pashkovskyy Valeryy, MD, PhD; Romaniv Olexander, MD; Skrypnikov Andrii, MD; Smolko Nadiya, MD, PhD; Statinova Olena, MD; Studzinskyy Oleg, MD; and Verbenko Viktoriya, MD, PhD.

Author contributions

KH was an investigator for this study. JSN and HRB were involved in the original study design and implementation. HMR and ASB were the (responsible) Medical Officers supervising the conduct of the study. JH was the study statistician. MS and BD contributed to the analysis and interpretation and critical revision of the manuscript for important intellectual content.

All authors contributed to the development of the manuscript and approved the final manuscript for submission. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors met the International Council of Medical Journal Editors’ criteria for authorship, and anyone who met those criteria is listed as an author.

Disclosure

The study was sponsored by Janssen Research and Development LLC, Raritan, New Jersey, USA.

ASB, JSN, JH, and HMR are employees of Janssen Research and Development, LLC; and HRB is an employee of Janssen Alzheimer Immunotherapy, LLC (both are Johnson and Johnson companies). All these authors hold stocks in Johnson and Johnson. MS is employed by The Mount Sinai Medical Center. She has provided consultation to Janssen Pharmaceuticals, Eli Lilly, Esai, Medivation, Sanofi Aventis, and Takeda. She has also consulted for Merck and Nutricia without any compensation. BD is the inventor of the use of galantamine to treat Alzheimer’s disease and is an employee and stockholder in Synaptec Inc., which licensed use of galantamine to Janssen. The authors report no other conflicts of interest in this work.