[Summary text]
Data obtained from:
Seitz, D. P.; Gill, S. S.; Herrmann, N.; Brisbin, S.; Rapoport, M. J.; Rines, J.; Wilson, K.; Le Clair, K.; Conn, D. K.
Pharmacological treatments for neuropsychiatric symptoms of dementia in long-term care: a systematic reviewInternational psychogeriatrics 2013;25(2):185-203England 2013
Data obtained from:
Wang, Jun; Yu, Jin-Tai; Wang, Hui-Fu; Meng, Xiang-Fei; Wang, Chong; Tan, Chen-Chen; Tan, Lan
Pharmacological treatment of neuropsychiatric symptoms in Alzheimer's disease: a systematic review and meta-analysisJournal of Neurology, Neurosurgery & Psychiatry 2015;86(1):101-109England 2015
Data obtained from:
Wang, Jun; Yu, Jin-Tai; Wang, Hui-Fu; Meng, Xiang-Fei; Wang, Chong; Tan, Chen-Chen; Tan, Lan
Pharmacological treatment of neuropsychiatric symptoms in Alzheimer's disease: a systematic review and meta-analysisJournal of Neurology, Neurosurgery & Psychiatry 2015;86(1):101-109England 2015
Data obtained from:
Wang, Jun; Yu, Jin-Tai; Wang, Hui-Fu; Meng, Xiang-Fei; Wang, Chong; Tan, Chen-Chen; Tan, Lan
Pharmacological treatment of neuropsychiatric symptoms in Alzheimer's disease: a systematic review and meta-analysisJournal of Neurology, Neurosurgery & Psychiatry 2015;86(1):101-109England 2015
Data obtained from:
Wang, Jun; Yu, Jin-Tai; Wang, Hui-Fu; Meng, Xiang-Fei; Wang, Chong; Tan, Chen-Chen; Tan, Lan
Pharmacological treatment of neuropsychiatric symptoms in Alzheimer's disease: a systematic review and meta-analysisJournal of Neurology, Neurosurgery & Psychiatry 2015;86(1):101-109England 2015
Study design: Randomized controlled trial
Study grouping: Parallel group
Included criteria: Eligible patientswere outpatients aged≥50 years with mild to moderate orsevere dementia (10 to 26 on the Mini-Mental StateExamination (MMSE) and Clinical Dementia Rating≥0.5)and behavioral and psychiatric symptoms (Neuropsychi-atric Inventory-plus (NPI-plus)≥8 and NPI (NPI-2)≥1).The NPI-plus consisted of 12 items: the original 10items, sleep [14,15] and cognitive fluctuation, which isreported as the Cognitive Fluctuation Inventory [16,17](see Additional file 1). The NPI-2 consisted of hallucina-tions and cognitive fluctuation [11]. The caregivers of theeligible patients had to routinely stay with them at least3 days per week and 4 hours per day, provide informationfor this study, assist with the compliance with treatmentand escort them to required visits.
Excluded criteria: The exclusion criteria included Parkinson’s diseasethat was diagnosed at least 1 year prior to the onset ofdementia; focal vascular lesions visualized on magnetic resonance imaging or computed tomographic scans thatmight cause cognitive impairment; other neurological orpsychiatric diseases; clinically significant systemic disease;complications or a history of severe gastrointestinal ulcer,severe asthma or obstructive pulmonary disease; systolichypotension (90 mmHg); bradycardia (50 m−1); sicksinus syndrome; atrial or atrioventricular conductionblock; QT interval prolongation (≥450 ms); hypersen-sitivity to donepezil or piperidine derivatives; severeparkinsonism (Hoehn and Yahr stage IV or above) [18];and treatment with ChEIs or any investigational drugwithin 3 months prior to screening. ChEIs, antipsychoticsand antiparkinson drugs other than L-dopa or dopamineagonists were not allowed during the study
Intervention Characteristics
Donepezil 5mg
Donepezil 10mg
Placebo
Serious adverse events, %
BPSD (NPI), SE
Data obtained from:
Seitz, D. P.; Gill, S. S.; Herrmann, N.; Brisbin, S.; Rapoport, M. J.; Rines, J.; Wilson, K.; Le Clair, K.; Conn, D. K.
Pharmacological treatments for neuropsychiatric symptoms of dementia in long-term care: a systematic reviewInternational psychogeriatrics 2013;25(2):185-203England 2013
and
Wang, Jun; Yu, Jin-Tai; Wang, Hui-Fu; Meng, Xiang-Fei; Wang, Chong; Tan, Chen-Chen; Tan, Lan
Pharmacological treatment of neuropsychiatric symptoms in Alzheimer's disease: a systematic review and meta-analysisJournal of Neurology, Neurosurgery & Psychiatry 2015;86(1):101-109England 2015
Wrong comparator
Wrong patient population
Abstract only
Wrong patient population
Wrong comparator
Wrong patient population
Abstract only
Wrong patient population
Wrong patient population
Wrong patient population
Wrong patient population
Wrong intervention
Abstract only
Wrong patient population
Abstract only
Duplicate
Wrong comparator
Wrong comparator
Wrong patient population
Wrong comparator
Wrong patient population
Wrong study design
Wrong study design
Wrong comparator
Wrong patient population
Wrong patient population
Wrong patient population
Wrong study design
Wrong patient population
Wrong patient population
Wrong study design
Wrong study design
Wrong patient population
Wrong patient population
Abstract only
Wrong patient population
Wrong patient population
Wrong patient population
Wrong patient population
Wrong patient population
Wrong patient population
Wrong patient population
Wrong patient population
Wrong patient population
Wrong intervention
Wrong patient population
Wrong patient population
Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence
reference: Seitz et al., 2013
Quote: "Participants were randomly assigned with equal probability to twice daily memantine 10 mg (titrated in 5 mg increments over four weeks) or placebo. Randomisation used a secure internet based randomisation service independent of the study team."
Judgement Comment: "Patients were randomly and equally allocated to one of the two treatment groups in accordance with randomization list generated by the sponsor following a standard routine"
Judgement Comment: Patients were randomized using a computer-genrated randomization protocol to placebo or 10mg/day donepezil on a 3:2 ratio
Quote: Telephone randomization was performed centrally by the Medical Research Council (MRC) Clinical Trials Unit. Assignment of treatment to drug-pack numbers was performed with the use of a random sequence of numbers (fixed blocks of six).
Quote: "Randomization was performed centrally according to a dynamic allocation, adjusting for MMSE and NPI-2 scores at screening."
reference: Seitz et al., 2013
Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment
reference: Seitz et al., 2013
Quote: "participants, study personnel, clinicians and carers were blind to allocation,"
Judgement Comment: Allocation concealment is not described
Judgement Comment: Randomization performed by an independent pharmacist who also provided numbered containers of identical tablets for each patient.
Quote: The data manager determined treatment as- signments using a fully blind minimization algo- rithm containing an embedded list of pack num- bers with corresponding treatment.
Judgement Comment: A member of the research staff whowas in charge of randomization and who was independentof all the parties concerned with the study securelykept the randomization list with limited access only inan emergency. No other members of the research staff,including the physicians, nurses and study institutionstaff were aware of the treatment assignment, nor wereany of the participants
reference: Seitz et al., 2013
Performance bias due to knowledge of the allocated interventions by participants and personnel during the study
reference: Seitz et al., 2013
Quote: "Blinding was achieved by using placebo and active drug identical in appearance and taste."
Judgement Comment: All participants, care providers and raters were blinded
Judgement Comment: All the patients where blinded, but it is unknown if the personnel were blinded
Quote: Clinicians, those administering the trial medication, patients, caregivers, and outcome assessors were all un- aware of the treatment assignments.
Judgement Comment: No other members of the research staff,including the physicians, nurses and study institutionstaff were aware of the treatment assignment, nor wereany of the participants.Patients received two study drug tablets, which werecomposed of a combination of 3 mg, 5 mg, or the matchedplacebo tablets with the same physical appearance, oncedaily in the morning
reference: Seitz et al., 2013
Detection bias due to knowledge of the allocated interventions by outcome assessors
reference: Seitz et al., 2013
Quote: "Since participants, study personnel, clinicians and carers were blind to allocation, no probabilistic element was introduced into the minimisation procedure. Blinding was achieved by using placebo and active drug identical in appearance and taste."
Judgement Comment: outcome assessors are blinded
Judgement Comment: The patients were outcome assessors and blinded
Quote: Clinicians, those administering the trial medication, patients, caregivers, and outcome assessors were all un- aware of the treatment assignments.
Quote: "No other members of the research staff, including the physicians, nurses and study institution staff were aware of the treatment assignment,"
Judgement Comment: as the potcome assessors were not aware of the intervention this could not affect the outcome
reference: Seitz et al., 2013
Attrition bias due to amount, nature or handling of incomplete outcome data
reference: Seitz et al., 2013
Quote: "The primary analysis was an intention to treat (ITT) analysis; participants were analysed as part of their allocated group irrespective of medication protocol adherence. Linear"
Judgement Comment: Reasons for dropouts are provided and ITT analyses performed
Judgement Comment: Reasons for drop out are provided, and equally destributed between groups:Memantine: 31 out of 182 discontinuatedPlacebo: 32 out of 187 discontinuated. Further, efficacy analyses were performed on the FAS, using the last observation carried forward approach
Judgement Comment: Reasons for drop out are provided and ITT analyses was performed
Judgement comment: 1 dropout in risperidone. 19 in placebo group. Reason for dropouts not explained
Judgement Comment: Describe incomplete data. Over sample study population.Detecting the significantdifference, predefined to be determined only with statisticalsignificance in both MMSE and NPI-2 results, withat least 80% statistical power between the placebo and5 mg groups required at least 126 patients (42 per group)(statistical power of 80.7%). The number was expected toprovide power of 85.4% to detect a significant differencebetween the placebo and 10 mg groups. Given that 10% ofthe patients were excluded from the full analysis set (FAS),the target number of patients in this study was set at 141
reference: Seitz et al., 2013
Reporting bias due to selective outcome reporting
reference: Seitz et al., 2013
Quote: "ClinicalTrials.gov NCT00371059"
Judgement Comment: Matches study protocol
Judgement Comment: Clinicaltrials.gov: NCT00857649.Matches study protocol
Judgement Comment: reference to study protocol, but not available. The study appears to be free of selective outcome reporting
Quote: ClinicalTrials.gov number, NCT00142324
Judgement comment: Matches study protocol
Judgement Comment: ClinicalTrials.gov Identifier: NCT01278407 No apparent sources of bias
reference: Seitz et al., 2013
Bias due to problems not covered elsewhere in the table
reference: Seitz et al., 2013
Judgement Comment: The study appears to be free of other sources of bias
Judgement Comment: The study appears to be free of other sources of bias
Judgement Comment: The study appears to be free of other sources of bias
Judgement comment: The study appears to be free of other sources of bias
Judgement Comment: Trial registration: Trial registration: ClinicalTrials.gov Identifier: NCT01278407 (trial registration date: 14 January 2011). No apparent sources of bias
reference: Seitz et al., 2013