Treatment Persistence and Real- World Effectiveness of Aripiprazole Once Monthly: A Four- Year Follow-Up


 ObjectivesTreatment persistence refers to the act of continuing a treatment as prescribed and reflects the patient's or doctor's judgment about efficacy, tolerability, and acceptability. In patients with schizophrenia, antipsychotic persistence is often poor, because of issues such as lack or loss of efficacy, side effects, and poor adherence, which is often related to the degree to which patients find the medication and overall intervention to be helpful, tolerable, fair, reasonable, appropriate, and consistent with expectations of treatment. Despite the poor antipsychotic persistence that has been reported to date in patients with schizophrenia, we previously observed a relatively high (86%) 6-month persistence with aripiprazole once-monthly (AOM) in a group of patients with schizophrenia, treated in the real world Italian clinical practice. The present study explores the longer-term persistence with AOM, over a mean follow-up period of 48 months MethodsThis was an observational, multicenter, retrospective, non-interventional follow-up study, aimed at evaluating the longer-term persistence with AOM in a group of patients with schizophrenia who had already shown persistence over a period of at least 6 months. The study included 161 individuals who had participated in our previous study, where 86% of participating individuals had shown persistence with AOM for at least 6 months. Non-persistence was defined as discontinuing the medication for any reason. Baseline demographic and clinical characteristics of patients who continued AOM were then compared to those of patients who discontinued the medication ResultsStudy subjects were predominantly male (64.4%) and their mean age was 39.7 (SD: 12.24). Treatment persistence with AOM was 69.6% and 112 out of 161 patients were still receiving AOM treatment at the last follow-up visit. The mean duration of AOM treatment until the last recorded observation was 55.87 months (median 56.17, SD6.23) for the 112 persistent patients and 32.23 (median 28.68.SD 15.09) months for the 49 non-persistent individuals. The mean observation period for all patients (persistent and non-persistent) was 48.78 months (median 52.54, SD 14.64). For non-persistent subjects, the observation period ended with the discontinuation of AOM. Subjects treated with AOM at 400 mg presented a 69.6% lower risk of all-cause treatment discontinuation when compared with patients treated with 300 mg (HR: 0.314; 95% confidence interval [CI]: 0.162-0.608; P=0.001). The main reasons for discontinuation were lack of efficacy (30.6%), patient/caregiver choice (18.4%), physician’s choice (16.3%), non-adherence (12.2%) and inconvenience (6.1%). Only 3 patients (6.1%) discontinued AOM for tolerability issues. ConclusionsIn subjects with schizophrenia, who had already shown a 6-month persistence with AOM, a high number of patients (69.6%) continued to be persistent over a four-year follow-up period. This may reflect a favourable profile of efficacy, tolerability, and acceptability. Larger and prospective studies are warranted to confirm our observations.


Introduction
Antipsychotic persistence refers to the act of continuing an antipsychotic as prescribed and re ects the patient's or healthcare provider's judgment about the e cacy, tolerability, acceptability, and perceived need for that medication (Ascher, 2008). Hence, causes of non-persistence to antipsychotics, include poor e cacy, poor tolerability, and poor adherence. We previously studied the 6-month persistence with aripiprazole once-monthly (AOM 400) in a group of 261 patients with schizophrenia recruited in the setting of the Italian National Public Health System (Fagiolini, 2009) and found that 86% percent of study subjects were persistent with AOM for at least 6 months. A similar study evaluated the 6-month AOM persistence, in 91 patients with schizophrenia treated in Spain. Six months after AOM initiation, 65 (71.4%) patients werepersistent, whereas 26 (28.6%) were not. The present study evaluates the treatment persistence in the same group of patients, over a longer period of time, along with the differences in clinical and demographic characteristics between patients who were or were not persistent with AOM for a period longer than 6 months. Methods DOMINO-I study was a non-interventional, retrospective, observational, multicenter study involving patients diagnosed with schizophrenia and aimed at evaluating the rate of persistence with AOM over a 6 -month period, along with the in uence of baseline demographic and clinical variables on the likelihood to be persistent (Fagiolini, 2009). The present study (DOMINO II) reports on a longer-term follow-up, over a mean period of 48.8 months from AOM initiation, involving the patients who were persistent for 6 months or longer in DOMINO-I study. Our primary objective was to evaluate the long-term persistence with AOM treatment, as de ned as being still on AOM at the time of the last follow-up observation. The secondary objectives included the evaluation of e cacy and tolerability. The study was approved by the Ethical Committee / Institutional Review Board at each recruitment site. Written informed consent was obtained from all participants or their legal guardians. The study was conducted between June 1, 2015 and November 23, 2020, in 16 clinical sites in Italy. All patients were at least 18 years old and carried a diagnosis of schizophrenia, as established via a clinical interview conducted to verify the presence of the Diagnostic and Statistical Manual for Mental Disorders, 5 th Edition (DSM 5) criteria.
Persistence was measured by time to all-cause AOM discontinuation and was assumed to re ect AOM's e cacy, safety, and tolerability from both patient and treating health care provider (HCP)'s perspectives.
Non-persistence was declared if the patient missed at least 2 consecutive or 3 non-consecutive injections of AOM. A missed dose of AOM was de ned as a lapse of more than 45 days from the previous AOM injection. Electronic and paper clinical records were reviewed and treating HCP were interviewed as per the date of AOM interruption or discontinuation and reasons, when applicable.

STATISTICAL METHODS:
The analyses were performed using Statistical Package for Social Science (SPSS-IBM, version 21.0 or later). Level of signi cance was set at a p-value <0.05 for two-tailed hypothesis. The "Full Analysis Set" (FAS) population was used to evaluate the primary objective. The FAS population included all patients persistent to AOM at the end of the DOMINO-I study observational period (6 months) for whom the information about the primary variables (long term persistence with AOM treatment) was available. The continuous variables were reported by sample statistics: n (number of observations), number of missing data, mean, standard deviation (SD), minimum, rst quartile (Q1), median, third quartile (Q3), and maximum. The summary statistics mean, median, standard deviation, minimum, maximum, Q1 and Q3 were presented to one more decimal places as that used to collect the data.
Treatment persistence, or retention rate (RR), was de ned as the proportion of patients who maintained the same medication (AOM) in a speci c period. Treatment persistence might be considered as a proxy for treatment e cacy and safety, given that lack of e cacy or poor tolerability are among the main reasons for discontinuation. As in DOMINO-I study, non-persistence was declared if a patient missed 2 consecutive or 3 non-consecutive injections of AOM during the retrospective follow-up period. Treatment persistence was evaluated using Kaplan Meier survival method. Person-years at risk were computed from the beginning of AOM treatment to the point of treatment discontinuation, end of the study (last retrospective assessment, scheduled to be completed by the end of November 2020), or loss to follow-up, whichever occurred rst. The event for "discontinuation" and the determination of RR was the interruption of AOM treatment. Patients lost to follow-up were considered as censored. The starting time for the Kaplan Meier analysis was the index date (date of AOM initiation).
Using a Cox Regression model demographic and clinical characteristics were evaluated for their effect on the long-term persistence to AOM. The variables included in the model were sourced from medical records or directly veri ed with the patients: age, gender, marital status, education, occupation, living situation and family support, number of previous acute episodes, schizophrenia, comorbidities, history of non-adherence in the 3 months prior to the index date, alcohol and/or drug abuse, reason to initiate AOM treatment, last antipsychotic treatment prior to AOM, CGI-S at index date and starting AOM dose.
Prior to the main analysis of the primary objective, univariate analyses (Chi Square tests, Student T tests or Mann-Whitney tests, as applicable) were performed to test the association between demographic and clinical characteristics of patients and long-term persistence with AOM (each baseline variable was compared between patients still in treatment at the end of the long-term follow-up period and patients that interrupted/discontinued the treatment before long term follow-up visit).
Univariate and multivariate Hazard Ratios (HR) with 95% Con dence Intervals (CIs) were calculated by regression model in which demographic and clinical characteristics were the independent variables and persistence was the dependent variable. The Cox Regression model produces a survival function that predict the probability of the discontinuation (event of interest) occurrence at a given time t for given predictor variable values. The shape of the survival function and the regression coe cients for the predictors were estimated from observed subjects. Cox's semi-parametric model was used in the data analysis to explain the effect of explanatory variables on hazard rates.

Secondary objectives
The FAS population was used to evaluate all the secondary objectives. The analysis of the secondary objectives was essentially descriptive. Data was presented using summary statistics. All categorical variables were summarized in frequency and percentage. The continuous variables were reported by sample statistics: n (number of observations), number of missing data, mean, SD, minimum, Q1, median, Q3, and maximum. The summary statistics mean, median, standard deviation, minimum, maximum, Q1 and Q3 were presented to one more decimal places as that used to collect the data.
CGI-Severity score (index date, DOMINO-I inclusion visit date, long term follow-up visit date) was compared using the non-parametric Wilcoxon Signed-Rank test. The test is a non-parametric analogous of the One-Sample t-test. This test can be used to make inferences about a population mean or median, without requiring the assumption of normally distributed data. Additionally, all CGI-Severity score data collected for each patient after the index date, were analyzed descriptively.

Results
Two-hundred-twenty-ve (225) patients persistent to AOM at the end of the DOMINO-I study observational period were eligible to participate in this study. The same chronological inclusion order was followed, based on DOMINO-I patient log archived at each site. One-hundred-sixty-one subjects were included in this study. Sixty-four patients did not participate because four DOMINO-I sites declined to participate in DOMINO-II study or because of insu cient data quality. Study subjects (n=161) were predominantly male (64.4%) and their mean age was 39.7 (SD: 12.24).
Treatment persistence with AOM was 69.6% and 112 out of 161 patients were still receiving AOM treatment at the last follow-up visit (Figure 1). The mean duration of treatment was 55.87 months (median 56.17, SD6.23) for persistent patients, and 32.23 (median 28.68.SD 15.09) months for nonpersistent patients (p< 0.001). For non-persistent patients, the follow-up ended at the time of AOM discontinuation. The mean observation period following AOM initiation in the entire group of patients (persistent and non-persistent) was 48.78 months (median 52.54, SD 14.64).
No signi cant difference was found between persistent and non-persistent patients for: age at AOM initiation, age at the last follow up visit, gender, education, marital status, occupation, age at rst schizophrenia diagnosis, time since schizophrenia onset, number of relapses in the previous 5 years, alcohol or drug abuse.
The multivariate model showed that: 3. Patients who lived in a psychiatric assisted living facility presented an 83.0% lower risk of discontinuation when compared with patients who lived alone, or with their family (HR: 0.170; 95% con dence interval [CI]: 0.023-1.236; P=0.080). Table 2 and Table 3 report the Clinical Global Impression scores at intake and at the last follow-up observation, and the difference between persistent and non-persistent individuals.
CGI score improved from baseline to the last follow up visit in 59 (49.2%) of the 120 patients whose CGI was recorded both at intake and at the follow up visit. CGI score worsened in 24 (20.0%) and did not change in the remaining 37 (30.8%) patients.
The percentage of patients whose CGI worsened was higher (34.9% vs. 11.7%) in the non-persistent patients.
Forty-nine patients discontinued the medication during the observed follow-up period. The main reasons for discontinuation were lack of e cacy (30.6%), patient/caregiver choice (18.4%), physician's choice (16.3%), non-adherence (12.2%) and inconvenience (6.1%). Only 3 patients (6.1%) discontinued AOM for tolerability issues. Three patients died during the period covered by the study. In none of the three cases, the death was related to AOM.

Discussion
Treatment persistence re ects the patient's or clinician's judgment about the prescribed medication. [HF1] In patients with schizophrenia, treatment persistence is often undermined by lack or loss of e cacy, poor tolerability, non-adherence or poor adherence to treatment (Velligan, 2010; Weiden, 1995, Kirson, 2013, Brissos, 2014. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial evaluated 1432 patients with schizophrenia, who were randomly assigned to receive olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone for up to 18 months. The study demonstrated that 74 percent of patients (1061 out of 1432) discontinued the study medication before 18 months: 64 % of those assigned to olanzapine, 75 % of those assigned to perphenazine, 82 % of those assigned to quetiapine, 74 % of those assigned to risperidone, and 79 % of those assigned to ziprasidone. Hence, only 26% of patients were persistent for 18 months, with their prescribed antipsychotic.
While the comparative e cacy of antipsychotic medications is sensitive to research design, long-acting antipsychotics have frequently displayed signi cant advantages over the oral formulations in real world, observational, studies (Kishimoto 2021). Results from randomized placebo-controlled trials are less consistent but this may be at least partially due to the possibility that the research procedures and settings of randomized, placebo controlled trials, reduces the risk of non-adherence to oral medications (Kirson, 2013).
Also, patients who agree to participate in a randomized and placebo-controlled clinical trial are usually more likely to be adherent to the prescribed medication, compared with patients that are treated in the real world setting. In fact, the structured setting of a randomized and placebo-controlled trial, likely reduces the rates of non-adherence, given its relatively intense monitoring and assessments schedules and, when allowed, the presence of incentives and reimbursements (Shirley et al, 2014).
AOM combines the advantages of depot antipsychotics, for instance in terms of improving adherence, with a proven e cacy and a relatively benign tolerability pro le (Mustafa et al, 2019).
That we observed that 69.6% of patients were still persistent after 48 months of AOM treatment, with only 30,4% of AOM patients that did not continue the medication for at least 48 months, con rms our hypothesis that AOM is a medication that is associated with a high persistence rate, not only for the short period (as demonstrated in our previous 6 month persistence study) but also for the longer term. We believe that this may be correlated with the relatively benign tolerability pro le of AOM, along with the high degree of adherence usually associated with long acting antipsychotics, and the e cacy as a long term preventative medication (Mustafa, 2019; Kirson, 2013;Kaplan, 2013). Interestingly, we noted that patients treated with an AOM dose of 400 mg presented a 69.6% lower risk of all-cause treatment discontinuation when compared with patients treated with a dose of 300 mg (HR: 0.314; 95% CI: 0.162-0.608; P=0.001), this suggesting the possibility that the higher dose (400 mg) might have greater e cacy than 300 mg. However, the reasons why patients were on 300 mg was not recorded and therefore we cannot exclude that patients were prescribed the 300 mg dose because they were more sensitive to side effects, which could increase the likelihood of a following discontinuation.