[Summary text]
Study design: Randomized controlled trial
Study grouping: Parallel group
Baseline Characteristics
Overall
Included criteria: Patients were male or female, aged 40 years andabove, resided in long-term nursing homes or continu-ing-care hospitals in Europe, Australia, Israel, Lebanon, and South Africa, and were expected tocontinue patient status for 6 months following enroll-ment. All patients met the NINCDS-ADRDA (McKhannet al., 1984) and DSM-IV-TR (AmericanPsychiatric Association, 2000) criteria for possible or probable Alzheimer’s disease (AD), and all exhib-ited clinically significant psychotic symptoms (delu-sions or hallucinations) due to AD. The delusions or hallucinations had to: (1) be at least moderate in severity (i.e. impair patients’ functional capacity or cause them to pose a threat to themselves) at study entry (Visit 1) and at randomization (Visit 2); (2) be present at least once per week for the month preced-ing study entry; and (3) require pharmacological intervention, in the opinion of the investigator. Aminimum score of 5 on the Mini-Mental State Exam-ination (MMSE; Folsteinet al., 1975) was required at Visit 1 and Visit 2.
Excluded criteria: Exclusionary criteria included a diagnosis of current primary mood disorder or other Axis I disorder with onset prior to diagnosis of AD, including but not limited to schizophrenia, bipolar disorder, or delusional disorder.
Pretreatment: Patient demographics and illness characteristics at baselinewere not statistically different among treatment groups
Intervention Characteristics
Intervention 1
Intervention 2
Control
Serious adverse events, n
Mortality, n
BPSD (NPI), SD
Study design: Randomized controlled trial
Study grouping: Parallel group
Baseline Characteristics
Overall
Included criteria: Noninstutitionalized men and women, aged 55-95 years of age, diagnosed with AD, with symptoms of delusions or hallucinations present for 1 month or longer. MMSE score of 6-24, and NPI delusion/halluciation at baseline of >= 6.
Excluded criteria: Diagnosis of delirium, amnesic disorder, bipolar disorder, schizophrenia or schizoaffective disorder or mood disorder with psychotic feature, psychotic symptom better accounted for by general medical condition or direct psychologic effects of substances. Refractory to neuroleptics used to treat psychotic symptoms in the past.
Pretreatment: Patient characteristics were similar between groups at baseline.
Intervention Characteristics
Intervention
Control
Serious adverse events, n
BPSD (NPI), SD
Kognition (MMSE), SD
Study design: Randomized controlled trial
Study grouping: Parallel group
Baseline Characteristics
Intervention 1
Intervention 2
Control
Included criteria: Men and women, age 55-95 years, diagnosed with AD and psychotic symptoms of delusions or hallucinations, living in nursing homes or residential assisted-living facilities for a minimum of 4 weeks before study entry. Patients required to be capable of selflocomotion and have an identified proxy caregiver.
Excluded criteria: Axis 1 diagnosis of delirium, amnestic disorder, bipolar disorder, schizophrenia or schizoaffective disorder, or mood disorder with psychotic features; non-AD: a current MD episode with psychotic symptoms of hallucinations or delusions.
Pretreatment: There were no apparent differences at baseline between the groups.
Intervention Characteristics
Intervention 1
Intervention 2
Control
Serious adverse events, n
Mortality, %
BPSD (NPI), SD
Kognition (MMSE), SD
Agitation (CMAI), SD
Study design: Randomized controlled trial
Study grouping: Parallel group
Baseline Characteristics
Intervention 1
Intervention 2
Intervention 3
Control
Included criteria: Patients must have scored 3 or higher on any of this items in the NPI
Excluded criteria: History of axis I disorder, any neurological condition other than AD that could be contribute to psychosis or dementia, a MMSE score of greater than 24 and beridden status.
Pretreatment: Patient characteristics were similar at baseline across groups
Intervention Characteristics
Intervention 1
Intervention 2
Intervention 3
Control
Serious adverse events, n
BPSD (NPI), SD
Kognition (MMSE), SD
Study design: Randomized controlled trial
Study grouping: Parallel group
Baseline Characteristics
Intervention
Control
Included criteria: Men and women aged 55-95 years, diagnosed with AD, had psychotic symptoms of delusions or hallucinations for =>1 month. Subjects had to be institutionalized for =>4 weeks before study entry, capable of self-locomotion or locomotion with aid and have caregiver or famility member who could serve as a collateral informant for study information. Patients were required to have a MMSE score between 6-22 at screening with a score of => 6 on either the delusions or hallucinations items of the NPI at baseline.
Excluded criteria: Axis 1 diagnosis of delerium or schizophrenia, a schizoaffective mood, bipolar or amnestic disorder, any reversible cause of dementia, continous symptoms of psychosis before onset of dementia, psychotic symptoms better accounted for by another medical condition or direct effects of a substance. Current episodes of MD with symptoms of psychosis; dementia resulting from vascular causes and specific non- AD type dementia caused by trauma, disease, infection or substance abuse, a seizure disorder and/or unstable thyroid pathology within the past 3 months. Previously refractory to antipsychotic medicin for psychosis, had participated in any clinical study with an investigational agent =1 month before randomization: had received recent treatment with a long-acting antipsychotic agent in which the last dose was administered 1 full cycle plus 1 week prior to randomization, met DSM-IC criteriafor any significant substance use disorder, were deemed to be a significant risk of suicide; were likely to require prohibited concomitant thereapy, were known to be allergic or hypersensitive to aripiprazole or quinolionens, had any laboratory test, vital sign or EEG abnormalities that could indicate elevated risk for significant adverse events or any medical condition that would make study partiticpation unsafe.
Pretreatment: Groups were similar at baseline
Intervention Characteristics
Intervention
Control
Serious adverse events, n
BPSD (NPI), SD
Kognition (MMSE), SD
ADL (ADCS-ADL), SD
Agitation (CMAI), SE
Study design: Randomized controlled trial
Study grouping: Parallel group
Baseline Characteristics
Overall
Included criteria: To participate in the trial, patients met DSM-IV criteria for dementia of the Alzheimer’s type(19) or met NINCDS-ADRDA criteria for probable AD (20), after a thorough history, physicaland cognitive examination, and laboratory assessment were completed. Enrolled patients wereoutpatients living at home or in an assisted-living facility, had a knowledgeable informant, andwere ambulatory. Patients in skilled nursing homes were not included. Mini-Mental State Exam(MMSE) (21) score was 5 to 26. Entry criteria required that delusions, hallucinations, agitation,or aggression had occurred nearly every day over the previous week or intermittently over 4 weeks. Symptoms had to have been rated at least moderate in severity on the Brief PsychiatricRating Scale (BPRS) conceptual disorganization, suspiciousness, or hallucinatory behavioritem, or had occurred at least weekly with moderate severity or greater on the delusion,hallucination, agitation, or aberrant motor behavior item of the Neuropsychiatric Inventory(NPI).Patients could be taking stable cholinesterase inhibitor medication; memantine had not been approved in the U.S. during the enrollment period.
Excluded criteria: Patients were excluded if they were takingantidepressants or anticonvulsants for mood stabilization
Pretreatment: There was no difference on any baseline symptom score across the treatment groups, except for NPI totalscore (p=0.02; ANOVA)
Intervention Characteristics
Intervention 1
Intervention 2
Intervention 3
Control
Serious adverse events, n
Mortality, n
BPSD (NPI), SD
Kognition (MMSE), SD
ADL (ADCS-ADL), SD
Quality of life
Study design: Randomized controlled trial
Study grouping: Parallel group
Baseline Characteristics
Intervention 1
Intervention 2
Control
Included criteria: Participants were residents of nursing homes and assistedliving facilities, enrolled between September 2002 andNovember 2003 from 53 centers in the United States. Theyhad diagnoses of probable or possible AD or vascular de-mentia according to Diagnostic and Statistical Manual ofMental Disorders – fourth edition [DSM-IV] or the NationalInstitute of Neurological and Communicative Disorders andStroke/the Alzheimer's Disease and Related Disorders Asso-ciation [NINCDS/ADRDA]) criteria. Other inclusion criteriawere as follows: minimum age of 55 years, ambulatory orambulatory with assistance, documented clinical symptomsof agitation that did not result directly from the participant’smedical condition and required treatment with antipsychoticmedication in the opinion of the investigator, a total score of>14 on the PANSS-EC and a score of >4 on one of the 5PANSS-EC items (hostility, tension, uncooperativeness, ex-citement, poor impulse control) both at screening and at ran-domization.
Excluded criteria: Key exclusion criteria included a history ofschizophrenia, schizoaffective disorder or bipolar disorder,agitation that was judged not to be related to dementia, fail-ure to respond to a prior adequate trial of atypical antipsy-chotics for the treatment of agitation, and unstable medicalillness (this included but was not limited to: cardiovascular,renal, hepatic, hematological, endocrine, and cerebrovasculardisorders). Any participants with abnormal ECG results thatwere considered clinically significant were also excludedfrom the study
Pretreatment: The demographic and baseline characteristics were simi-lar among the three treatment groups
Intervention Characteristics
Intervention 1
Intervention 2
Control
Serious adverse events, n
Mortality, %
BPSD (NPI), SD
Agitation (CMAI), SD
Wrong study design
Wrong patient population
Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence
Judgement Comment: Described as randomized, no details
Judgement Comment: Described as randomized, no details given
Judgement Comment: Described as randomized, no details
Judgement Comment: Randomization by the assignment of a unique kit number using a permuted block design at investigational site
Judgement Comment: Described as randomized, no details
Judgement Comment: Described as randomized, no details
Quote: "The centralized randomization schedule was generated using a random block size of 8 and was created using random seed and treatment allocation ratios of 3:3:2 and maintained blinded by the sponsor’s randomization group."
Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment
Judgement Comment: Described as randomized, no details
Judgement Comment: Described as randomized, no details given
Judgement Comment: Described as randomized, no details
Judgement Comment: Study medication was in identical tablets and dosed once daily.
Judgement Comment: Described as randomized, no details
Quote: "according to IRB guidelines. Treatments <b>Medications were prepared in low-dose and high-dose identically-appearing capsules that contained either olanzapine (2.5mg or 5mg), quetiapine (25mg or 50mg), risperidone (0.5mg or 1mg), or placebo.</b> The clinician selected the number"
Quote: "Medication was dis- tributed to centers in randomization blocks of 8. Each kit contained 10 blister wallets with the same number of tablets and the same configuration of color, size, and shape. Study medication was administered twice daily from blister wallets."
Performance bias due to knowledge of the allocated interventions by participants and personnel during the study
Judgement Comment: Placebo-controlled fixed dose
Judgement Comment: Described as double-blind, probable that the patients were blinded. Apripiprazole could be tritrated to higher dose if there was insufficient clinical response. The same is not described for placebo. Therefore it is unclear if the personnel was blinded.
Judgement Comment: Described as double-blind, placebo controlled fixed dose
Judgement Comment: Described as double-blind placebo controlled fixed dose
Judgement Comment: Described as double-blind. Aripiprazole dose was flexible, no details on placebo titrating
Judgement Comment: Described as 'double-blind'. Identical capsules so participants and personnel were probably blinded
Judgement Comment: Placebo controlled fixed dose
Detection bias due to knowledge of the allocated interventions by outcome assessors
Judgement Comment: Not described
Judgement Comment: Not described
Judgement Comment: No details
Judgement Comment: No details
Judgement Comment: Described as double-blind. Aripiprazole dose was flexible, no details on placebo titrating. No details on assessors
Judgement Comment: Not described
Attrition bias due to amount, nature or handling of incomplete outcome data
Judgement Comment: Percent completing ranged from 70.5 in the placebo group to 75.2 in the olanzapine groups. Reasons differed between group
Judgement Comment: 83% completed the treatment, reasons for withdrawal were similar
Judgement Comment: 487 randomized (4 groups), safety population 480, efficacy population 475
Judgement Comment: Proportion completed ranged from 66% to 80.4%, different reasons for drop out
Judgement Comment: In the placebo group 51% completed and in the aripiprazole group the number was 66%. The reasons differed.
Judgement Comment: High for ADL, MMSE and QoL. Low for SAE and death
Quote: "Two hundred and fifteen participants (65%) completed the study; the completion rates were com- parable among the three groups"
Reporting bias due to selective outcome reporting
Judgement Comment: None detected
Judgement Comment: None detected
Judgement Comment: None detected
Judgement Comment: No reporting on SAE or death
Judgement Comment: None detected
Judgement Comment: Match to protocol, except Beck Depression Inventory
Judgement Comment: None detected
Bias due to problems not covered elsewhere in the table
Judgement Comment: No other apparent sources of bias
Judgement Comment: No other apparent sources of bias
Judgement Comment: No other apparent sources of bias
Judgement Comment: No other apparent sources of bias
Judgement Comment: No other apparent sources of bias
Judgement Comment: No other apparant sources of bias
Judgement Comment: No other apparent sources of bias