The review protocol was not registered.
Randomized controlled trials of brexpiprazole and/or aripiprazole p.o. in patients with current diagnosis of acute exacerbation of schizophrenia aged ≥ 18 years were eligible for this review. The study duration was restricted to 4 or 6 weeks because a maintenance treatment for relapse prevention over 26 weeks or longer was reported in only one trial for each drug.
The following databases with DIMDI search interface (no longer available today) were used to identify eligible brexpiprazole studies: CCTR93 (Cochrane Central Register of Controlled Trials), ME60 (Medline), and EM74 and EA08 (Embase and Embase Alert). The DIMDI search was completed by searches in public clinical trials registries and databases: WHO ICTRP (International Clinical Trials Registry Platform), ClinicalTrials.gov, Pharmnet.Bund, EU Clinical Trials Register, LIVIVO, and Pubmed. One additional study  was provided by Lundbeck outside the searches shortly after publication in July 2018. The following databases were used to identify eligible aripiprazole studies: LIVIVO and Pubmed. This was completed by a search in the registry ClinicalTrials.gov.
The basic strategy to identify brexpiprazole studies in databases with DIMDI search interface is shown in Additional file 1. The search was performed by Lundbeck on 02 May 2015 and completed by searches in ICTRP, ClinicalTrials.gov, Pharmnet.Bund, and EU Clinical Trials Register on the same day. Later updates in ClinicalTrials.gov, LIVIVO, and Pubmed were performed by the CRO in April and May 2018.
Five brexpiprazole and five aripiprazole studies were suited for the 4 or 6 weeks treatment of patients with an acute exacerbation of schizophrenia. The studies were accepted with one placebo arm and one to three active treatment arms.
Data collection process
Data were extracted from brexpiprazole and aripiprazole full publications and study results in ClinicalTrials.gov, in one case supplemented by data from a poster presentation . Data were entered directly into SAS files by a member of the statistics department of the CRO, printouts of which were checked against the original sources by an independent person from data management. Any corrections were quality controlled by means of printouts of the corrected files.
The population of interest consists of adult patients (18 years or older) having a DSM-IV-TR diagnosis of schizophrenia confirmed by the Mini International Neuropsychiatric Interview (MINI) for Schizophrenia and Psychotic Disorders Studies. For studies which started before DSM-IV-TR was available an equivalent diagnosis can be sufficient.
In the group of potentially eligible trials, the following doses were administered: brexpiprazole 0.25, 1, 2, 2.5, 2 – 4, 4, 5 mg/day, aripiprazole 2, 5, 10, 15, 20 mg/day. However, the doses of 0.25 and 5 mg brexpiprazole as well as 2 and 5 mg aripiprazole were not considered in the review because 0.25 mg brexpiprazole is, though approved by the European Medicines Agency for patients taking strong metabolic inhibitors, not approved in Switzerland and is not a recommended dose, 5 mg brexpiprazole and 2 mg aripiprazole are not approved, and 5 mg aripiprazole is predominantly used in the elderly who were not included in the studies considered in this paper. Results are reported in the pool of all approved and recommended doses.
Placebo was the only comparator eligible for the meta-analysis.
In patients with acute schizophrenia the continuous outcome measures of this trial (PANSS, CGI) were commonly transformed into a responder criterion as follows:
- If CGI is not available: A response is defined as reduction from baseline in the PANSS Total score of ≥ 30%.
- If CGI is available: A response is defined as reduction from baseline in the PANSS Total score of ≥ 30% and/or CGI-I = 1 (very much improved) or CGI-I = 2 (much improved).
Further binary outcomes are:
- the number of completers
- total rates of adverse events, defined by 'adverse events', 'treatment-emergent adverse events', or 'other adverse events than serious adverse events'
- rates of serious adverse events
- rates of study discontinuation due to adverse events
- incidences of selected adverse events.
- S: items of study design
The following items were used to characterise the study design: trial centres, concealment / blinding, allocation / randomisation, phases / duration of phases, experimental design, type of comparison, sample size determination.
Risk of bias in individual studies
The Cochrane risk of bias tool was used to describe the risk of bias in individual studies. This tool consists of five items: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and a catch-all item called 'other sources of bias'.
The report used Hedges's g, odds ratios, risk ratios, and risk differences to quantify the effect sizes of summary measures. However, we focussed on binary outcomes which allow a comparison of benefits and harm. Therefore, only two meta-analyses (responder rates, total incidences of adverse events) are shown as examples, further analyses are based on NNT and NNH (see below).Synthesis of results
Fixed effect and random effects models are used in the meta-analyses, however, the main results are based on NNT and NNH (see below).
Additional statistical analyses
Typical outcomes of placebo-controlled clinical trials are the absolute increase of responder rates (AIR) and the absolute risk reduction (ARR) of adverse events. The number needed to be treated with active drug instead of placebo for one additional patient to benefit is defined by NNT = 1/AIR, the number needed to be treated with active drug instead of placebo for one additional patient to be harmed by NNH = 1/ARR. Significance tests of NNT or NNH can be performed by confidence limits. If, e.g., ARR is calculated as p1 – p0 (p1 = risk of active drug, p0 = risk of placebo) with 95% confidence limits Cllow and Clupp, then the lower limit LL = 1/Clupp and the upper limit UL = 1/Cllow can be used as confidence limits of NNH. The confidence interval Cllow ≤ p ≤ Clupp consists of positive values if Cllow > 0 and negative values if CIupp < 0. In these cases no problems occur with the interpretation of LL and UL. However, if zero is contained in the interval p1 – p0, the transformed interval of NNH consists of the intervals from
- –∞ to LL = 1/Clupp (maximum value: –1)
- and UL = 1/Cllow to +∞ (minimum value: +1)
In this case we do not discuss the confidence limits but only use the relevant information that the difference between p1 and p0 is not significant if the confidence limits of NNH have different directions. If the confidence interval of NNH consists of only negative values (i.e. a significantly lower harm was observed with active drug compared with placebo), one should interpret the lower harm as benefit. The likelihood to be helped or harmed, defined by LHH = NNH/NNT, can then be used to quantify the value –NNH as predictor of the responder rate. In general, the LHH describes how often benefits are encountered more frequently than harm.
Two methods are used to calculate confidence limits LL and UL: Wald and Wilson [11–18]. Wilson should be preferred in case of ARR values near 0 or 1 and small sample sizes, because the asymptotic method of Wald provides unreliable values in these situations.