Dement Geriatr Cogn Disord 2014;37:232–245 DOI: 10.1159/000355373 Accepted: June 28, 2013 Published online: November 14, 2013
© 2013 S. Karger AG, Basel 1420–8008/14/0374–0232$39.50/0 www.karger.com/dem
Original Research Article
Phase II Crossover Trial of Varenicline in Mild-to-Moderate Alzheimer’s Disease Seong Yoon Kim a Seong Hye Choi b Hans Rollema c Tom McRae d Sarah Dubrava d Janice Jacobsen d
Elias M. Schwam d
a Department of Psychiatry, Asan Medical Center, Seoul, and b Department of Neurology, Inha University School of Medicine, Incheon, South Korea; c Rollema Biomedical Consulting, Mystic, Conn., and d Pfizer Inc., Groton, Conn., USA
Key Words Alzheimer’s disease · Cognition · Crossover study · Partial agonist · Receptor activation · Varenicline
Seong Yoon Kim, MD, PhD Department of Psychiatry, Asan Medical Center 388-1, Poongnap-2dong Songpa-gu, Seoul 138-736 (South Korea) E-Mail sykim @ amc.seoul.kr
Downloaded by: Kellogg Health Sciences Libr. 129.173.72.87 - 5/18/2015 11:22:48 AM
Abstract Background: Evidence supports a role of α4β2 receptors in Alzheimer’s disease (AD). Methods: This Korean, multicenter, double-blind, two-period (6 weeks each), crossover study randomized participants to the order in which they received varenicline (1 mg twice daily) and placebo. Assessments included AD Assessment Scale-Cognitive Subscale (ADAS-Cog) 75, Neuropsychiatric Inventory (NPI), adverse events (AEs) and Columbia-Suicide Severity Rating Scale (C-SSRS). Results: For varenicline versus placebo (n = 66 randomized), there was no significant difference in the week 6 least square (LS) mean ADAS-Cog 75 total score (primary endpoint; 18.07 vs. 18.49; p = 0.3873) and a slight worsening in the week 6 LS mean NPI (3.82 vs. 2.55; p = 0.0468), primarily driven by decreased appetite/eating. Common treatment-related AEs were nausea (23.3; 3.4%), vomiting (15.0%; 0) and decreased appetite (15.0; 6.8%). Conclusions: Varenicline did not improve cognition, behavior or global change in this population. The most frequent varenicline-associated AEs were gastrointestinal; psychiatric AEs were rare and similar between the groups. © 2013 S. Karger AG, Basel
233
Dement Geriatr Cogn Disord 2014;37:232–245 DOI: 10.1159/000355373
© 2013 S. Karger AG, Basel www.karger.com/dem
Kim et al.: Phase II Crossover Trial of Varenicline in Mild-to-Moderate Alzheimer’s Disease
Alzheimer’s disease (AD) – a neurodegenerative disorder of the brain characterized by progressive memory loss, behavioral and personality disturbances, and deficits in performing activities of daily living – is the leading cause of dementia [1]. It is well known that the central cholinergic system plays an important role in cognitive function, and study results suggest that α4β2 [2, 3] and α7 [4–7] nicotinic acetylcholine receptors (nAChRs) are involved in the pathophysiology of AD. For example, the cognitive deficits that occur in patients with AD are accompanied by a marked loss of α4β2 nAChRs [2, 3], and a study in Chinese patients with AD revealed that mRNA levels of α4 and β2 nAChR subunits significantly correlated with cognitive test scores [8]. Early clinical studies suggested that α4β2 nAChR agonists have the potential to improve cognition in these patients. A small study in patients with moderate AD reported that the full agonist, ABT-418, improved total recall and reduced recall failure on a verbal learning task [9], and a study in healthy male volunteers reported that the partial agonist, ispronicline (TC-1734, AZD3480), was associated with a significant enhancement of attention and episodic memory versus placebo [10]. Furthermore, ispronicline was shown to have a beneficial effect on cognition in elderly patients with age-associated memory impairment [11, 12]. However, recent results from large trials in patients with AD have not confirmed the initial positive results. For example, transdermally administered ABT-418 lacked efficacy in a placebo-controlled trial as reported by Arneric et al. [13], and ispronicline did not meet the primary endpoint of change from baseline in AD Assessment ScaleCognitive Subscale (ADAS-Cog) score in patients with mild-to-moderate AD (although secondary endpoints were improved) [14]. While these compounds are all selective α4β2 agonists, their binding affinities, functional activities and pharmacokinetic properties vary, and it remains unknown whether these compounds have the optimal properties to be effective as treatments for AD. Varenicline tartrate is a selective α4β2 nAChR partial agonist that is approved worldwide as a smoking cessation aid at a dose of 1 mg twice daily (BID) for 12 weeks starting with a 1-week up-titration [15, 16]. Varenicline binds to α4β2 nAChRs (Ki 0.1–0.4 nM) with much higher affinity than to other subtypes (>200-fold for α3β4, α7 and α6* nAChRs; >20,000-fold for α1βγδ receptors) and has very low affinity (Ki >350 nM) for other, nonnicotinic receptors and binding sites [17–19]. Several preclinical models of cognition and attention suggested a potential benefit of varenicline at exposures comparable with those for smoking cessation [20], and initial clinical studies appeared to confirm these findings. A small prospective study in 14 smokers with schizophrenia revealed that varenicline was associated with significant improvements in cognitive test scores for verbal learning and memory [21]. Varenicline also improved cognition in smokers who were actively seeking to quit [22], and prevented exacerbation of cognitive defects in male smokers with diagnosed schizophrenia [23]. Varenicline has an affinity at least an order of magnitude higher at α4β2 nAChRs than other α4β2 nAChR partial agonists investigated in cognition trials, and has predictable pharmacokinetic properties with a straightforward dispositional profile [24]. The pharmacokinetic and adverse event (AE) profiles of varenicline in elderly smokers [25] and nonsmokers [26] (aged >65 years, with normal renal function for their age) have been shown to be generally comparable with those in healthy smokers aged 18–65 years [27]. As such, varenicline was a promising candidate for investigation in improvement of cognition in patients with AD. Here, we report the results of a proof-of-concept study, conducted in patients with mild-to-moderate probable AD using the varenicline dose (1 mg BID) recommended for smoking cessation, to determine whether varenicline was efficacious compared with placebo on relevant symptom domains, primarily cognition.
Downloaded by: Kellogg Health Sciences Libr. 129.173.72.87 - 5/18/2015 11:22:48 AM
Introduction
234
Dement Geriatr Cogn Disord 2014;37:232–245 DOI: 10.1159/000355373
© 2013 S. Karger AG, Basel www.karger.com/dem
Kim et al.: Phase II Crossover Trial of Varenicline in Mild-to-Moderate Alzheimer’s Disease
Methods Study Design This phase 2, multicenter, randomized, double-blind, placebo-controlled, crossover study was conducted at eight research centers in the Republic of Korea between July 29, 2009 and November 10, 2010. The study consisted of a 3-week screening period (week –6 to week –3), a 3-week single-blind placebo run-in period (week –3 to baseline), and two 6-week, double-blind treatment periods (period 1 and period 2) separated by a 3-week, single-blind, placebo washout. A total treatment duration of 6 weeks was chosen based on previous studies, which reported a clinically significant effect with donepezil at 6 weeks [28–30]. This study was a proof-of-concept trial, and a short-term, placebo, crossover design was chosen to enable detection of a signal after 6 weeks of treatment with varenicline. Typically, the desired signal is a decline in the placebo group, which often does not occur until 12 weeks, but for this proof-of-concept study, an improvement in the varenicline group after 6 weeks of treatment was considered an appropriate signal for feasibility to move forward with the study program. A 3-week washout period was considered appropriate in relation to the half-life of varenicline. Subjects were randomized to one of two treatment sequences – varenicline followed by placebo (varenicline-first group) or placebo followed by varenicline (placebo-first group) – using block randomization with stratification by mild and moderate AD based on Mini-Mental State Examination (MMSE) scores of 21–26 and 14–20, respectively. Written informed consent was obtained from all participants. Consent forms and procedures were approved by institutional review boards at each site. The study was conducted in compliance with the ethical principles of the Declaration of Helsinki and the standards on good clinical practice according to the International Conference on Harmonization.
Study Procedures All participants were assessed during the 3-week screening period (week –6 to week –3) for the following: medical history; history of drug, alcohol and tobacco use; physical examination; vital signs; electrocardiogram; serum pregnancy test (for women of childbearing potential); blood chemistry; hematology; urinalysis; MMSE score, and modified Hachinski scale. All subjects received placebo during the 3-week single-blind run-in period (week –3 to baseline), followed by two 6-week double-blind treatment periods (period 1 and period 2) of active and placebo treatment in a randomized sequence. Treatment periods were separated by a 3-week single-blind placebo washout. Efficacy assessments were conducted at baseline, week 1, week 3 and week 6 (or early termination) of each treatment period. Safety assessments were conducted at baseline and at each postrandomization visit. Blood samples (3 ml) for the measurement of varenicline concentrations were collected from each subject at the week 1, week 3 and week 6 (or early termination) visits of each treatment period. Sampling was performed immediately following completion of the cognitive testing at weeks 1 and 3, and following completion of all study procedures at week 6 of each treatment period. Plasma samples were analyzed using a validated, sensitive and specific assay as previously described [27].
Downloaded by: Kellogg Health Sciences Libr. 129.173.72.87 - 5/18/2015 11:22:48 AM
Screening and Eligibility Subjects were outpatients between the ages of 55 and 85 years with diagnostic evidence of probable AD consistent with the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) [31] and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria [32]. Subjects must also have had mild-to-moderate AD with an MMSE score [33] of between 14 and 26 (inclusive) at screening, and magnetic resonance imaging or a computed tomography scan within the preceding 12 months consistent with a diagnosis of probable AD without any other clinically significant comorbid pathologies. Subjects must have had a modified Hachinski ischemic scale score ≤4 [34]. Exclusion criteria included evidence or history of neurological, psychiatric or any other illness that could contribute to dementia (including, but not limited to, other neurodegenerative disorders): severe depression warranting a concurrent diagnosis other than AD; rating of ‘severe’ and a frequency of more than ‘occasionally’ on the Neuropsychiatric Inventory (NPI) [35] item for delusions, agitation/aggression, anxiety or depression/dysphoria at screening; creatinine clearance
© 2013 S. Karger AG, Basel 1420–8008/14/0374–0232$39.50/0 www.karger.com/dem
Original Research Article
Phase II Crossover Trial of Varenicline in Mild-to-Moderate Alzheimer’s Disease Seong Yoon Kim a Seong Hye Choi b Hans Rollema c Tom McRae d Sarah Dubrava d Janice Jacobsen d
Elias M. Schwam d
a Department of Psychiatry, Asan Medical Center, Seoul, and b Department of Neurology, Inha University School of Medicine, Incheon, South Korea; c Rollema Biomedical Consulting, Mystic, Conn., and d Pfizer Inc., Groton, Conn., USA
Key Words Alzheimer’s disease · Cognition · Crossover study · Partial agonist · Receptor activation · Varenicline
Seong Yoon Kim, MD, PhD Department of Psychiatry, Asan Medical Center 388-1, Poongnap-2dong Songpa-gu, Seoul 138-736 (South Korea) E-Mail sykim @ amc.seoul.kr
Downloaded by: Kellogg Health Sciences Libr. 129.173.72.87 - 5/18/2015 11:22:48 AM
Abstract Background: Evidence supports a role of α4β2 receptors in Alzheimer’s disease (AD). Methods: This Korean, multicenter, double-blind, two-period (6 weeks each), crossover study randomized participants to the order in which they received varenicline (1 mg twice daily) and placebo. Assessments included AD Assessment Scale-Cognitive Subscale (ADAS-Cog) 75, Neuropsychiatric Inventory (NPI), adverse events (AEs) and Columbia-Suicide Severity Rating Scale (C-SSRS). Results: For varenicline versus placebo (n = 66 randomized), there was no significant difference in the week 6 least square (LS) mean ADAS-Cog 75 total score (primary endpoint; 18.07 vs. 18.49; p = 0.3873) and a slight worsening in the week 6 LS mean NPI (3.82 vs. 2.55; p = 0.0468), primarily driven by decreased appetite/eating. Common treatment-related AEs were nausea (23.3; 3.4%), vomiting (15.0%; 0) and decreased appetite (15.0; 6.8%). Conclusions: Varenicline did not improve cognition, behavior or global change in this population. The most frequent varenicline-associated AEs were gastrointestinal; psychiatric AEs were rare and similar between the groups. © 2013 S. Karger AG, Basel
233
Dement Geriatr Cogn Disord 2014;37:232–245 DOI: 10.1159/000355373
© 2013 S. Karger AG, Basel www.karger.com/dem
Kim et al.: Phase II Crossover Trial of Varenicline in Mild-to-Moderate Alzheimer’s Disease
Alzheimer’s disease (AD) – a neurodegenerative disorder of the brain characterized by progressive memory loss, behavioral and personality disturbances, and deficits in performing activities of daily living – is the leading cause of dementia [1]. It is well known that the central cholinergic system plays an important role in cognitive function, and study results suggest that α4β2 [2, 3] and α7 [4–7] nicotinic acetylcholine receptors (nAChRs) are involved in the pathophysiology of AD. For example, the cognitive deficits that occur in patients with AD are accompanied by a marked loss of α4β2 nAChRs [2, 3], and a study in Chinese patients with AD revealed that mRNA levels of α4 and β2 nAChR subunits significantly correlated with cognitive test scores [8]. Early clinical studies suggested that α4β2 nAChR agonists have the potential to improve cognition in these patients. A small study in patients with moderate AD reported that the full agonist, ABT-418, improved total recall and reduced recall failure on a verbal learning task [9], and a study in healthy male volunteers reported that the partial agonist, ispronicline (TC-1734, AZD3480), was associated with a significant enhancement of attention and episodic memory versus placebo [10]. Furthermore, ispronicline was shown to have a beneficial effect on cognition in elderly patients with age-associated memory impairment [11, 12]. However, recent results from large trials in patients with AD have not confirmed the initial positive results. For example, transdermally administered ABT-418 lacked efficacy in a placebo-controlled trial as reported by Arneric et al. [13], and ispronicline did not meet the primary endpoint of change from baseline in AD Assessment ScaleCognitive Subscale (ADAS-Cog) score in patients with mild-to-moderate AD (although secondary endpoints were improved) [14]. While these compounds are all selective α4β2 agonists, their binding affinities, functional activities and pharmacokinetic properties vary, and it remains unknown whether these compounds have the optimal properties to be effective as treatments for AD. Varenicline tartrate is a selective α4β2 nAChR partial agonist that is approved worldwide as a smoking cessation aid at a dose of 1 mg twice daily (BID) for 12 weeks starting with a 1-week up-titration [15, 16]. Varenicline binds to α4β2 nAChRs (Ki 0.1–0.4 nM) with much higher affinity than to other subtypes (>200-fold for α3β4, α7 and α6* nAChRs; >20,000-fold for α1βγδ receptors) and has very low affinity (Ki >350 nM) for other, nonnicotinic receptors and binding sites [17–19]. Several preclinical models of cognition and attention suggested a potential benefit of varenicline at exposures comparable with those for smoking cessation [20], and initial clinical studies appeared to confirm these findings. A small prospective study in 14 smokers with schizophrenia revealed that varenicline was associated with significant improvements in cognitive test scores for verbal learning and memory [21]. Varenicline also improved cognition in smokers who were actively seeking to quit [22], and prevented exacerbation of cognitive defects in male smokers with diagnosed schizophrenia [23]. Varenicline has an affinity at least an order of magnitude higher at α4β2 nAChRs than other α4β2 nAChR partial agonists investigated in cognition trials, and has predictable pharmacokinetic properties with a straightforward dispositional profile [24]. The pharmacokinetic and adverse event (AE) profiles of varenicline in elderly smokers [25] and nonsmokers [26] (aged >65 years, with normal renal function for their age) have been shown to be generally comparable with those in healthy smokers aged 18–65 years [27]. As such, varenicline was a promising candidate for investigation in improvement of cognition in patients with AD. Here, we report the results of a proof-of-concept study, conducted in patients with mild-to-moderate probable AD using the varenicline dose (1 mg BID) recommended for smoking cessation, to determine whether varenicline was efficacious compared with placebo on relevant symptom domains, primarily cognition.
Downloaded by: Kellogg Health Sciences Libr. 129.173.72.87 - 5/18/2015 11:22:48 AM
Introduction
234
Dement Geriatr Cogn Disord 2014;37:232–245 DOI: 10.1159/000355373
© 2013 S. Karger AG, Basel www.karger.com/dem
Kim et al.: Phase II Crossover Trial of Varenicline in Mild-to-Moderate Alzheimer’s Disease
Methods Study Design This phase 2, multicenter, randomized, double-blind, placebo-controlled, crossover study was conducted at eight research centers in the Republic of Korea between July 29, 2009 and November 10, 2010. The study consisted of a 3-week screening period (week –6 to week –3), a 3-week single-blind placebo run-in period (week –3 to baseline), and two 6-week, double-blind treatment periods (period 1 and period 2) separated by a 3-week, single-blind, placebo washout. A total treatment duration of 6 weeks was chosen based on previous studies, which reported a clinically significant effect with donepezil at 6 weeks [28–30]. This study was a proof-of-concept trial, and a short-term, placebo, crossover design was chosen to enable detection of a signal after 6 weeks of treatment with varenicline. Typically, the desired signal is a decline in the placebo group, which often does not occur until 12 weeks, but for this proof-of-concept study, an improvement in the varenicline group after 6 weeks of treatment was considered an appropriate signal for feasibility to move forward with the study program. A 3-week washout period was considered appropriate in relation to the half-life of varenicline. Subjects were randomized to one of two treatment sequences – varenicline followed by placebo (varenicline-first group) or placebo followed by varenicline (placebo-first group) – using block randomization with stratification by mild and moderate AD based on Mini-Mental State Examination (MMSE) scores of 21–26 and 14–20, respectively. Written informed consent was obtained from all participants. Consent forms and procedures were approved by institutional review boards at each site. The study was conducted in compliance with the ethical principles of the Declaration of Helsinki and the standards on good clinical practice according to the International Conference on Harmonization.
Study Procedures All participants were assessed during the 3-week screening period (week –6 to week –3) for the following: medical history; history of drug, alcohol and tobacco use; physical examination; vital signs; electrocardiogram; serum pregnancy test (for women of childbearing potential); blood chemistry; hematology; urinalysis; MMSE score, and modified Hachinski scale. All subjects received placebo during the 3-week single-blind run-in period (week –3 to baseline), followed by two 6-week double-blind treatment periods (period 1 and period 2) of active and placebo treatment in a randomized sequence. Treatment periods were separated by a 3-week single-blind placebo washout. Efficacy assessments were conducted at baseline, week 1, week 3 and week 6 (or early termination) of each treatment period. Safety assessments were conducted at baseline and at each postrandomization visit. Blood samples (3 ml) for the measurement of varenicline concentrations were collected from each subject at the week 1, week 3 and week 6 (or early termination) visits of each treatment period. Sampling was performed immediately following completion of the cognitive testing at weeks 1 and 3, and following completion of all study procedures at week 6 of each treatment period. Plasma samples were analyzed using a validated, sensitive and specific assay as previously described [27].
Downloaded by: Kellogg Health Sciences Libr. 129.173.72.87 - 5/18/2015 11:22:48 AM
Screening and Eligibility Subjects were outpatients between the ages of 55 and 85 years with diagnostic evidence of probable AD consistent with the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) [31] and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria [32]. Subjects must also have had mild-to-moderate AD with an MMSE score [33] of between 14 and 26 (inclusive) at screening, and magnetic resonance imaging or a computed tomography scan within the preceding 12 months consistent with a diagnosis of probable AD without any other clinically significant comorbid pathologies. Subjects must have had a modified Hachinski ischemic scale score ≤4 [34]. Exclusion criteria included evidence or history of neurological, psychiatric or any other illness that could contribute to dementia (including, but not limited to, other neurodegenerative disorders): severe depression warranting a concurrent diagnosis other than AD; rating of ‘severe’ and a frequency of more than ‘occasionally’ on the Neuropsychiatric Inventory (NPI) [35] item for delusions, agitation/aggression, anxiety or depression/dysphoria at screening; creatinine clearance
