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Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease: A Randomized Clinical Trial.

ABSTRACT: Importance:Oligomeric amyloid-? peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease. Objective:To determine whether AZD0530 treatment slows the decline in cerebral metabolic rate for glucose (CMRgl) and is safe and well tolerated. Design, Setting, and Participants:This multicenter phase 2a randomized clinical trial enrolled participants between December 23, 2014, and November 30, 2016. Participants (n?=?159) had mild Alzheimer dementia and positron emission tomography (PET) evidence of elevated levels of amyloid-? peptide. Efficacy analyses of all primary and secondary outcomes were conducted in a modified intention-to-treat population. Final analyses were conducted from February 9, 2018, to July 25, 2018. Interventions:AZD0530 (100 mg or 125 mg daily) vs placebo for 52 weeks. Main Outcomes and Measures:Primary outcome was the reduction in relative CMRgl, as measured by 18F-fluorodeoxyglucose (18F-FDG) PET, at 52 weeks in an Alzheimer disease-associated prespecified statistical region of interest. Secondary end points included change in cognition, function, and other biomarkers. Results:Among the 159 participants, 79 were randomized to receive AZD0530 and 80 to receive placebo. Of the 159 participants, 87 (54.7%) were male, with a mean (SD) age of 71.0 (7.7) years. Based on a week-2 plasma drug level (target?=?180 ng/mL; 30nM free), 15 participants (19.2%) had their AZD0530 dose escalated from 100 mg to 125 mg. Mean plasma levels from weeks 13 to 52 were 220 ng/mL and 36nM free. More participants discontinued treatment with AZD0530 than with placebo (21 vs 11), most commonly because of adverse events. The most frequent adverse events were gastrointestinal disorders (primarily diarrhea), which occurred in 38 participants (48.1%) who received AZD0530 and in 23 (28.8%) who received placebo. In the primary outcome, the treatment groups did not differ in 52-week decline in relative CMRgl (mean difference: -0.006 units/y; 95% CI, -0.017 to 0.006; P?=?.34). The treatment groups also did not differ in the rate of change in Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Clinical Dementia Rating, Neuropsychiatric Inventory, or Mini-Mental State Examination scores. Secondary volumetric magnetic resonance imaging analyses revealed no treatment effect on total brain or ventricular volume but did show trends for slowing the reduction in hippocampal volume and entorhinal thickness. Conclusions and Relevance:Statistically significant effects of AZD530 treatment were not found on relative CMRgl reduction in an Alzheimer disease-associated region of interest or on secondary clinical or biomarker measures. Trial Registration:ClinicalTrials.gov identifier: NCT02167256.

SUBMITTER: van Dyck CH

PROVIDER: S-EPMC6646979 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease: A Randomized Clinical Trial.

van Dyck Christopher H CH Nygaard Haakon B HB Chen Kewei K Donohue Michael C MC Raman Rema R Rissman Robert A RA Brewer James B JB Koeppe Robert A RA Chow Tiffany W TW Rafii Michael S MS Gessert Devon D Choi Jiyoon J Turner R Scott RS Kaye Jeffrey A JA Gale Seth A SA Reiman Eric M EM Aisen Paul S PS Strittmatter Stephen M SM

JAMA neurology 20191001 10

<h4>Importance</h4>Oligomeric amyloid-β peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease.<h4>Objective</h4>To determine whether AZD0530 treatment slows the decline in cerebral metabolic rate for glucose (CMRgl) and is safe and well tolerated.<h4> ...[more]

PMID: 31329216

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Project description:ImportanceAgitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory.ObjectiveThe primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability.Design, setting, and participantsThe Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013.InterventionsParticipants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability.Main outcomes and measuresPrimary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events.ResultsParticipants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was -0.93 (95% CI, -1.80 to -0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (-1.05 points; 95% CI, -1.97 to -0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group.Conclusions and relevanceAmong patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day.Trial registrationclinicaltrials.gov Identifier: NCT00898807.

Project description:ContextDocosahexaenoic acid (DHA) is the most abundant long-chain polyunsaturated fatty acid in the brain. Epidemiological studies suggest that consumption of DHA is associated with a reduced incidence of Alzheimer disease. Animal studies demonstrate that oral intake of DHA reduces Alzheimer-like brain pathology.ObjectiveTo determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease.Design, setting, and patientsA randomized, double-blind, placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination scores, 14-26) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer's Disease Cooperative Study.InterventionParticipants were randomly assigned to algal DHA at a dose of 2 g/d or to identical placebo (60% were assigned to DHA and 40% were assigned to placebo). Duration of treatment was 18 months.Main outcome measuresChange in the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and change in the Clinical Dementia Rating (CDR) sum of boxes. Rate of brain atrophy was also determined by volumetric magnetic resonance imaging in a subsample of participants (n = 102).ResultsA total of 402 individuals were randomized and a total of 295 participants completed the trial while taking study medication (DHA: 171; placebo: 124). Supplementation with DHA had no beneficial effect on rate of change on ADAS-cog score, which increased by a mean of 7.98 points (95% confidence interval [CI], 6.51-9.45 points) for the DHA group during 18 months vs 8.27 points (95% CI, 6.72-9.82 points) for the placebo group (linear mixed-effects model: P = .41). The CDR sum of boxes score increased by 2.87 points (95% CI, 2.44-3.30 points) for the DHA group during 18 months compared with 2.93 points (95% CI, 2.44-3.42 points) for the placebo group (linear mixed-effects model: P = .68). In the subpopulation of participants (DHA: 53; placebo: 49), the rate of brain atrophy was not affected by treatment with DHA. Individuals in the DHA group had a mean decline in total brain volume of 24.7 cm(3) (95% CI, 21.4-28.0 cm(3)) during 18 months and a 1.32% (95% CI, 1.14%-1.50%) volume decline per year compared with 24.0 cm(3) (95% CI, 20-28 cm(3)) for the placebo group during 18 months and a 1.29% (95% CI, 1.07%-1.51%) volume decline per year (P = .79).ConclusionSupplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease.Trial registrationclinicaltrials.gov Identifier: NCT00440050.

Project description:ImportanceAlthough vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD.ObjectiveTo determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor.Design, setting, and participantsDouble-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers.InterventionsParticipants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152).Main outcomes and measuresAlzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures.ResultsData from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, -0.24 to 4.20; adjusted P = .40) than the placebo group's decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of "infections or infestations," with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants).Conclusions and relevanceAmong patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden.Trial registrationclinicaltrials.gov Identifier: NCT00235716.

Project description:Blood levels of homocysteine may be increased in Alzheimer disease (AD) and hyperhomocysteinemia may contribute to disease pathophysiology by vascular and direct neurotoxic mechanisms. Even in the absence of vitamin deficiency, homocysteine levels can be reduced by administration of high-dose supplements of folic acid and vitamins B(6) and B(12). Prior studies of B vitamins to reduce homocysteine in AD have not had sufficient size or duration to assess their effect on cognitive decline.To determine the efficacy and safety of B vitamin supplementation in the treatment of AD.A multicenter, randomized, double-blind controlled clinical trial of high-dose folate, vitamin B(6), and vitamin B(12) supplementation in 409 (of 601 screened) individuals with mild to moderate AD (Mini-Mental State Examination scores between 14 and 26, inclusive) and normal folic acid, vitamin B(12), and homocysteine levels. The study was conducted between February 20, 2003, and December 15, 2006, at clinical research sites of the Alzheimer Disease Cooperative Study located throughout the United States.Participants were randomly assigned to 2 groups of unequal size to increase enrollment (60% treated with high-dose supplements [5 mg/d of folate, 25 mg/d of vitamin B(6), 1 mg/d of vitamin B(12)] and 40% treated with identical placebo); duration of treatment was 18 months.Change in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog).A total of 340 participants (202 in active treatment group and 138 in placebo group) completed the trial while taking study medication. Although the vitamin supplement regimen was effective in reducing homocysteine levels (mean [SD], -2.42 [3.35] in active treatment group vs -0.86 [2.59] in placebo group; P < .001), it had no beneficial effect on the primary cognitive measure, rate of change in ADAS-cog score during 18 months (0.372 points per month for placebo group vs 0.401 points per month for active treatment group, P = .52; 95% confidence interval of rate difference, -0.06 to 0.12; based on the intention-to-treat generalized estimating equations model), or on any secondary measures. A higher quantity of adverse events involving depression was observed in the group treated with vitamin supplements.This regimen of high-dose B vitamin supplements does not slow cognitive decline in individuals with mild to moderate AD.clinicaltrials.gov Identifier: NCT00056225.

Project description:ImportanceNetwork hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD).ObjectiveTo determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD.Design, setting, and participantsThe Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini-Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination.InterventionsGroup A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence.Main outcomes and measuresThe primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer's Disease Assessment Scale-Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity.ResultsOf 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, 0.07 points; 95% CI, -0.18 to 0.32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, 0.2-14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = 0.11; P = .02). There were no treatment discontinuations because of adverse events.Conclusions and relevanceIn this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD.Trial registrationClinicalTrials.gov Identifier: NCT02002819.

Project description:ImportanceApathy is a frequent neuropsychiatric symptom in dementia of Alzheimer type and negatively affects the disease course and patients' and caregivers' quality of life. Effective treatment options are needed.ObjectiveTo examine the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type.Design, setting, and participantsThis 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial was conducted in a psychiatric and neurological outpatient setting between July 2010 and July 2014 in Germany. Patients with mild-to-moderate dementia of Alzheimer type and clinically relevant apathy were included. Patients with additional clinically relevant depressed mood were excluded. Data analyses were performed between August 2018 and August 2019.InterventionsPatients received either bupropion or placebo (150 mg for 4 weeks plus 300 mg for 8 weeks). In case of intolerability of 300 mg, patients continued to receive 150 mg throughout the study.Main outcomes and measuresChange on the Apathy Evaluation Scale-Clinician Version (AES-C) (score range, 18-72 points) between baseline and week 12 was the primary outcome parameter. Secondary outcome parameters included measures of neuropsychiatric symptoms, cognition, activities of daily living, and quality of life. Outcome measures were assessed at baseline and at 4, 8, and 12 weeks.ResultsA total of 108 patients (mean [SD] age, 74.8 [5.9] years; 67 men [62%]) were included in the intention-to-treat analysis, with 54 randomized to receive bupropion and 54 randomized to receive placebo. The baseline AES-C score was comparable between the bupropion group and the placebo group (mean [SD], 52.2 [8.7] vs 50.4 [8.2]). After controlling for the baseline AES-C score, site, and comedication with donepezil or galantamine, the mean change in the AES-C score between the bupropion and placebo groups was not statistically significant (mean change, 2.22; 95% CI, -0.47 to 4.91; P = .11). Results on secondary outcomes showed statistically significant differences between bupropion and placebo in terms of total neuropsychiatric symptoms (mean change, 5.52; 95% CI, 2.00 to 9.04; P = .003) and health-related quality of life (uncorrected for multiple comparisons; mean change, -1.66; 95% CI, -3.01 to -0.31; P = .02) with greater improvement in the placebo group. No statistically significant changes between groups were found for activities of daily living (mean change, -2.92; 95% CI, -5.89 to 0.06; P = .05) and cognition (mean change, -0.27; 95% CI, -3.26 to 2.73; P = .86). The numbers of adverse events (bupropion group, 39 patients [72.2%]; placebo group, 33 patients [61.1%]) and serious adverse events (bupropion group, 5 patients [9.3%]; placebo group, 2 patients [3.7%]) were comparable between groups.Conclusions and relevanceAlthough it is safe, bupropion was not superior to placebo for the treatment of apathy in patients with dementia of Alzheimer type in the absence of clinically relevant depressed mood.Trial registrationEU Clinical Trials Register Identifier: 2007-005352-17.

Dataset Information

Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease: A Randomized Clinical Trial.

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Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease: A Randomized Clinical Trial.

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