Improvement of functioning in patients with schizophrenia: Real-world effectiveness of aripiprazole once-monthly (REACT study)

doi:10.21203/rs.3.rs-2500860/v1

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Improvement of functioning in patients with schizophrenia: Real-world effectiveness of aripiprazole once-monthly (REACT study)

https://doi.org/10.21203/rs.3.rs-2500860/v1

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published 31 May, 2023

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Background: Functional impairment affects many patients with schizophrenia. Treatment with the long-acting injectable antipsychotic aripiprazole once-monthly (AOM) may help improve functioning.

Methods: Here we report functional outcomes in the form of Global Assessment of Functioning (GAF) scores in a pooled analysis of data from two non-interventional studies from Canada and Germany. Data from 396 patients were analyzed.

Results: At baseline, the mean GAF score was 47.7 (SD 13.4). During six months of treatment with AOM, the mean GAF score increased to 59.4 (SD 15.8). Subgroups stratified by patient age (≤35 years/>35 years), gender, disease duration (≤5 years/>5 years) and disease severity at baseline had all significantly improved their GAF at month 6. 51.5% of the patients showed a GAF score increase of at least 10 points, which was regarded as clinically meaningful, and were considered responders.

Conclusions: These data show that treatment with AOM may help improve patient functioning in a routine treatment setting.

Canadian Non-Interventional Trial Registration 06/05/2014 (NCT02131415).

Germany Non-Interventional Trial Registration 02/07/2014 (15960N).

Schizophrenia

long-acting injectable

non-interventional study

real-world evidence

Aripiprazole once-monthly

functioning

Functioning is impaired in many patients with schizophrenia. Impairment of functioning in schizophrenia is difficult to treat and should be a priority target for interventions [1], as this is an area of great unmet need [2]. A meta-analysis that investigated how many patients show adequate psychosocial functioning together with symptomatic remission for a timespan of at least 2 years found that this was only the case for 13.5% of patients [3].

Aripiprazole once-monthly (AOM) is an atypical antipsychotic in a long-acting injectable formulation, which provides reliable medication delivery, stable pharmacokinetics, and a means of monitoring for non-adherence [4]. The efficacy of AOM for relapse prevention in schizophrenia was demonstrated in two pivotal randomized controlled trials (RCTs) over 52 and 38 weeks respectively [5, 6]. In these trials, patient functioning was assessed using the Personal and Social Performance (PSP) scale [7] in patients previously stabilized with oral aripiprazole. In the 52-week study, mean total PSP scores from baseline were significantly worsened from baseline with placebo (from 69.4, standard error [SE] 0.97, to 63.2, SE 1.37) compared to AOM (from 68.0, SE 0.76, to 66.6, SE 0.89) in the double-blind treatment phase (p < 0.001)[8]. In the 38-week study, mean PSP total scores worsened significantly from baseline with AOM 50 mg (subtherapeutic dose, from 65.6, SE 1.18, to 64.6, SE 1.54) compared to AOM 400 mg (from 65.3, SE 0.70, to 65.9, SE 0.82) (p < 0.05) [8]. However, RCTs provide a somewhat artificial treatment setting and exclude the wide range of patients that are treated in real life, such as those with comorbidities who require multiple medications [9]. A recent cohort study has found that 79% of patients with schizophrenia encountered in real life would be ineligible for RCTs [10]. This renders the generalizability of the findings questionable in clinical practice. Therefore, real-world studies are an important complement to RCTs. In several real-world studies, patients with schizophrenia were found to show improvements in functioning over time when treated with AOM [11].

Here, we present pooled data from two non-interventional studies conducted in Germany [12, 13] and Canada [14] that assessed the functioning of outpatients with schizophrenia treated with AOM using the Global Assessment of Functioning (GAF) scale. Analyses of effectiveness outcomes have already been reported: for the total population, the mean Brief Psychiatric Rating Scale total score decreased from 48.1 (standard deviation [SD] 15.6) at baseline to 36.5 (SD 13.7) at month 6 (p < 0.001). Clinical Global Impression – Severity decreased from 4.47 (SD 0.90) at baseline to 3.64 (SD 1.16) at month 6 (p < 0.001) [15]. The main objective of the current paper was to determine whether the GAF scores improved over this 6-month period. The secondary-exploratory objectives were to examine whether the changes in GAF scores occurred in subgroups of patients defined according to age, male or female patients, duration of illness and severity of illness, which was made possible by the increased sample size resulting from analysis of both studies together. Additionally, we focused on response and remission of patient functioning, which are patient-relevant outcomes that had not been addressed previously.

We conducted post-hoc analyses of pooled data from two prospective non-interventional studies in which patients with schizophrenia from Canada (Trial registration 06/05/2014 (NCT02131415)) [14] and Germany (Trial registration 02/07/2014 (15960N)) [12, 13] were treated with AOM. In the current analysis, we included all patients who had received AOM treatment and for whom a GAF assessment at baseline and at least one time point post-baseline was available. 396 patients (228 out of 242 from Germany, 168 out of 169 from Canada) were therefore included in the analysis.

In the Canadian non-interventional study, adult patients (at least 19 years old for patients from British Columbia) who were at least mildly ill (Clinical Global Impression – Severity [CGI-S]-score of at least 3) could be included after the treating physician had prescribed AOM. The patients were treated at 17 Canadian community or hospital-based centers. Patients who were unable to provide informed consent, presented contraindications for AOM, had been treated with AOM previously, showed significant suicidal risk, or were pregnant or lactating, were excluded from the study. AOM treatment was to be initiated as per Canadian product label. For patients with no prior use of aripiprazole, tolerability had to be established with oral aripiprazole. After the first injection, oral aripiprazole was to be taken concomitantly for 2 weeks and then discontinued. The study was originally designed to assess functioning outcome at the end of 2 years. However, it was terminated early after at least 50% of the initially planned number of patients had completed the 12-month assessment. This decision was made by the study sponsor in consultation with the investigators. In the present analyses, only data from the first six months were extracted to make pooling with the German study data feasible.

In the German non-interventional study, outpatients who had been diagnosed with schizophrenia according to ICD-10 were eligible for inclusion if they were currently treated with a fixed dose of oral aripiprazole as per German product label. Patients who presented with contraindications for AOM, were members or were related to a member of the study staff, were pregnant or planned a pregnancy, were breastfeeding, or were expected to show reluctance to follow the prespecified monitoring plan (as assessed by the treating psychiatrist), were excluded from the study. The treating physician decided on the switch to AOM. Patients were to be switched to AOM as per German product label, i.e. patients had to be treated with a fixed dose of oral aripiprazole before the first injection and be considered clinically stable. After the first AOM injection, oral aripiprazole was to be taken concomitantly for 2 weeks and then discontinued. 75 treatment centers in Germany provided participant data. The planned study duration was 6 months.

GAF was an endpoint in both studies. GAF data from visits at baseline, month 3 and month 6 were pooled from both studies and are analyzed here. The GAF rates the individual’s overall functioning in the form of a single value between 1 and 100 (a score of 0 indicates insufficient information). The scale range is grouped in intervals of 10 points each. Descriptors are given in text form for each interval, with the lowest (1-10 points) described as “patient is in persistent danger of hurting self or others, or is persistently unable to maintain minimal personal hygiene, or recently performed a serious suicidal act with a clear expectation of death” and the highest (91-100 points) described as “superior functioning in a wide range of activities, no symptoms”. The treating physician is asked to first identify the appropriate 10-point interval and then select a score within the interval.

We defined a response on the GAF as an improvement by at least 10 points, matching the descriptor intervals on the GAF scale. In additional sensitivity analyses, we also looked at patients who reached a new 10-point interval on the GAF, irrespective of the number of points gained. For instance, a patient starting at 48 points at baseline and reaching 52 points at month 6 would be counted in this sensitivity analysis. Possible criteria for functional remission on the GAF may be scores of >60 [16, 17], or >80 points [18, 19]. We therefore analyzed the proportion of patients reaching these scores at 6 months.

We used the Wilcoxon signed rank test for paired samples, and the Wilcoxon rank sum test for independent samples. Missing values were imputed using the Last Observation Carried Forward (LOCF) method if there was a value for baseline and at least one post-baseline time point. All tests were two-sided with alpha = 0.05, with no correction for multiple testing for secondary outcomes. Subgroups were defined according to age (according to the ≤35 and >35-year cutoff used in the QUAlity of LIFe with AbiliFY Maintena® (QUALIFY) study [20]), gender, disease duration (≤5 years and >5 years) and disease severity defined according to the baseline CGI ratings.

GAF scores were available for 396 patients. Demographics and baseline characteristics for these patients are shown in table 1.

Table 1: Demographics and baseline characteristics of patients with evaluable GAF scores.

	Total population (n = 396)
Age (years), mean (SD)	38.7 (14.6)
Gender male, n (%)	238 (60.1)
Body Mass Index (kg/m²), mean (SD)	29.2 (6.9)
Age at diagnosis (years), mean (SD)	29.1 (11.6)
Duration of disease since diagnosis (years), mean (SD)	9.6 (10.2)
BPRS score at baseline, mean (SD)	48.1 (15.6)
CGI-S score at baseline, mean (SD)	4.47 (0.90)
GAF score at baseline, mean (SD)	47.7 (13.4)

BPRS, Brief Psychiatric Rating Scale; CGI-S, Clinical Global Impression – Severity; GAF, Global Assessment of Functioning; SD, standard deviation.

We compared the data of the original studies to see if they were similar enough to support pooling. Relevant GAF data are given in table 2.

Table 2: GAF data from the original studies.

Patients with baseline assessment	Patients from Canadian NIS (n = 169)	Patients from German NIS (n = 238)	p-value
GAF at baseline, mean (SD)	48.7 (12.6)	46.9 (13.9)
Patients with baseline and at least one post-baseline assessment	Patients from Canadian NIS (n = 168)	Patients from German NIS (n = 228)
GAF at baseline, mean (SD)	48.7 (12.6)	47.0 (13.9)	0.22^a
GAF at month 6, mean (SD)	58.0 (13.8)	60.5 (17.1)	0.04^a
Responders with improvement by at least 10 points, n (%)	75 (44.6)	129 (56.6)	0.02^b

^aWilcoxon Two-sample test; ^bFisher’s exact test. GAF, Global Assessment of Functioning; SD, standard deviation; NIS, non-interventional study.

Total population

In the analyzed population (n = 396), the mean GAF score at baseline was 47.7 (SD 13.4) [95% confidence interval [95% CI], 46.4-49.0] (figure 1). During six months of treatment with AOM, the mean GAF score increased to 59.4 (SD 15.8) [95% CI, 57.9-61.0]. Compared to baseline, improvements at month 3 and month 6 were statistically significant (p < 0.001).

Patients ≤35 years and >35 years

Patients ≤35 years started out with a mean GAF score of 49.0 (SD 12.7) [95% CI, 47.2-50.8] at baseline, while patients >35 years had a mean GAF score of 46.4 (SD 13.9) [95% CI, 44.5-48.3] (figure 2). Patients ≤35 years improved by 13.3 points (SD 16.4) [95% CI, 10.9-15.6] during 6 months of AOM treatment, reaching a mean score of 62.3 (SD 15.1) [95% CI, 60.1-64.4], compared to an improvement of 10.3 points (SD 13.9) [95% CI, 8.4-12.2] in patients >35 years, who reached a mean score of 56.7 (SD 16.1) [95% CI, 54.5-59.0].

Patient gender

At baseline, male patients had a mean GAF score of 48.0 (SD 13.4) [95% CI, 46.3-49.7], while female patients had a mean GAF score of 47.2 (SD 13.3) [95% CI, 45.1-49.3] (figure 3). During 6 months of treatment with AOM, male patients improved by 10.3 points (SD 14.8) [95% CI, 8.5-12.2] and reached a mean score of 58.4 (SD 15.8) [95% CI, 56.3-60.4], while female patients improved by 13.9 points (SD 15.8) [95% CI, 11.4-16.4] and reached a mean score of 61.1 (SD 15.8) [95% CI, 58.6-63.5].

Disease duration

Patients with a disease duration of ≤5 years had a mean GAF score of 47.9 (SD 13.5) [95% CI, 45.9-49.9] at baseline, while patients with a disease duration of >5 years had a mean GAF score of 47.6 (SD 13.3) [95% CI, 45.8-49.4] (figure 4). Patients with a disease duration of ≤5 years improved by 12.8 points (SD 16.3) [95% CI, 10.4-15.2] during 6 months of AOM treatment, reaching a mean score of 60.7 (SD 15.9) [95% CI, 58.4-63.0]. Patients with a disease duration of >5 years improved by 10.9 (SD 14.3) [95% CI, 9.0-12.8], reaching a mean of 58.5 (SD 15.6) [95% CI, 56.4-60.6] at month 6.

Baseline severity

Patients with greater disease severity at baseline had on average lower GAF scores than patients with less severe disease (figure 5). Patients with all levels of disease severity improved on the GAF during treatment, and intergroup differences decreased during treatment. Whereas higher CGI scores seem to correlate with greater improvements on the GAF scale, no significance was determined.

Responders

51.5% of the patients improved by at least 10 points, which corresponds to one descriptor interval on the GAF during 6 months, and were considered “responders” (figure 6). Among patients ≤35 years, 56.2% achieved a 10-point improvement, and among patients >35 years this was the case for 47.0%. Sensitivity analyses based on higher cut-offs revealed that 96 patients (24.2%) achieved an improvement of 20 points or more, 60 patients (15.2%) 30 points or more, and 28 patients (7.1%) 40 points or more.

For further sensitivity analysis, we looked at the proportion of patients in the total sample that moved to a higher descriptor interval during 6 months, irrespective of the actual number of points gained. This was the case for 250 patients (63.1%). 114 patients (28.8%) remained within the same interval during 6 months, and 32 patients (8.1%) moved to a lower interval. These changes did not depend on the baseline GAF score.

Composite responders

40.5% of the patients were considered “responders” on both the GAF scale and the Brief Psychiatric Rating Scale (BPRS) (figure 7), which means that they improved by at least 10 points on the GAF and by at least 20% on the BPRS. Among patients ≤35 years of age, 43.8% met the composite response criterion, which was true of only 37.3% of patients >35 years of age.

Functional remission

We analyzed the proportion of patients reaching >60, >70, or >80 points on the GAF at 6 months, representing possible criteria for functional remission. 179 patients (45.2%) reached >60 points, 82 patients (20.7%) reached >70 points, and 36 patients (9.1%) reached >80 points.

In our current analysis of pooled data from two non-interventional studies we found that, on average, patients experienced functional improvements during 6 months of treatment with AOM. Similar results were found when subgroups of patients were analyzed. This shows that in a routine treatment setting AOM can contribute to better functional outcomes in younger as well as older patients, male as well as female patients, patients with shorter or longer disease duration and patients with various degrees of disease severity. Furthermore, many of the patients in our sample had been pre-treated with oral antipsychotics at the time of entry into the two studies, and most patients of the German population had been considered symptomatically stable at study start [12]. Under these circumstances, AOM would be expected to show a stabilizing effect that prevents patients from deteriorating. However, we saw not only maintenance of previous levels of functioning, but further improvements as well. This is a noteworthy finding.

51.5% of the patients were considered “responders” at 6 months of AOM treatment, with improvements of at least 10 points on the GAF scale. They reached a higher 10-point interval on the GAF scale, with a new descriptor, which shows that the improvement is clinically relevant and makes a difference for the patient. Response on the GAF scale was often seen together with symptomatic response (defined as ≥20% BPRS improvement). However, what constitutes a clinically relevant change on the GAF is not well defined. Amri and colleagues have proposed 4, 10 or 12 points as possible criteria for clinical relevance [21], therefore, even a difference of 4 points should be clearly discerned by the treating physician. Here, a criterion of 10 points was chosen, which seems reasonable as the GAF scale intervals span 10 points each, and it can be assumed that these are even more clearly discernible. In a sensitivity analysis, we found that 63.1% of the patients reached a higher interval on the GAF, irrespective of the number of points gained.

The definition of an adequate level of functioning is also unclear, as there are not even established standards for people not afflicted by disease [22]. Studies have used several different cutoffs on the GAF scale for functional remission, including >60 [16, 17], or >80 [18, 19] points on the GAF. In our study, 45.2% of the patients reached >60 points at month 6, the softest possible criterion, 20.7% of the patients reached >70 points, and 9.1% patients reached >80 points, fulfilling the most conservative remission criterion.

The GAF is a validated functioning scale [23] that has been shown to provide a high inter-rater and test-retest reliability [24, 25]. However, the GAF has been criticized because it may measure symptoms rather than functioning if the symptomatic burden is considered more severe than the functional impairment [24–26]. Furthermore, being a single global measure it does not capture the complexity of functioning, many areas of which may or may not be affected in patients with schizophrenia (activities of daily living, vocation, family relationships, social relationships, finances, leisure activities, self-care) [27].

Limitations

All analyses done here have to be considered as post-hoc. There were some differences in baseline characteristics between the samples, with Canadian patients on average being significantly younger (p < 0.001) and less severely ill (p < 0.001) at baseline. Because of this, a feasibility analysis was done beforehand, which showed that pooling the data would produce valid results. Further limitations of our study are due to the real-world, uncontrolled, unblinded design of the original studies. A causal relationship of our results with the treatment cannot be concluded due to the lack of a comparator group. Confounders cannot be identified or excluded. Many of the patients (mainly and primarily those from Germany) had been treated with oral aripiprazole before inclusion in the study, potentially enriching the sample with patients who tolerated aripiprazole. Furthermore, patients may have had expectation bias since they were aware of the treatment and willing to try AOM. Real-world studies are nonetheless an important complement to RCTs [9, 10].

Our work here showed that patients with schizophrenia, treated with AOM in everyday clinical conditions, may experience clinically relevant functional improvements. These data add support to the body of evidence demonstrating the robust effectiveness of AOM in schizophrenia.

AOM – Aripiprazole once-monthly

BPRS – Brief Psychiatric Rating Scale

CGI-S - Clinical Global Impression – Severity

GAF – Global Assessment of Functioning

ICD-10 – International Statistical Classification of Diseases and Related Health Problems, 10th revision

LOCF – Last Observation Carried Forward

NIS – non-interventional study

PSP – Personal and Social Performance

QUALIFY - QUAlity of LIFe with AbiliFY Maintena®

RCT – Randomized controlled trial

REACT – REAl-world effeCTiveness of aripiprazole once-monthly

SD – Standard deviation

Ethics approval and consent to participate

The German non-interventional trial was designed according to the German Medicinal Products Act and approved by the Freiburg ethics commission international (Approval number: 014/1336). Each site involved in the Canadian ReliAM Trial obtained ethics approval from their local institutional ethics board. All patients enrolled in either non-interventional trial signed an informed consent before any study related procedures were performed. All methods involving the study was carried out according to rules/regulations/ in Accordance with Declaration of Helsinki.

Consent for publication

Not applicable.

Availability of data and materials

The datasets analyzed during the current study are not publicly available due to data from Canadian patients being property of Lundbeck Canada Inc. and Otsuka Canada Pharmaceutical Inc. but are available from the corresponding author on reasonable request.

Competing interests

OO has worked as a consultant, advisor and presented for Purdue, Sunovion, Pfizer, AbbVie/Allergan, Janssen Pharm., HLS Pharm., and Otsuka/Lundbeck Alliance.

GC was an employee of Lundbeck Canada Inc. at the time of writing.

WJ is an employee of Lundbeck GmbH.

DS received honoraria for lectures from, or has been an advisor to, Janssen GmbH, Lundbeck GmbH, Otsuka Pharma GmbH, Rovi and Takeda.

FT is an employee of Otsuka Canada Pharmaceutical Inc.

KW received honoraria for lectures and advisory board participation from Janssen-Cilag GmbH, Lundbeck GmbH and Otsuka GmbH.

MAR received investigator research grants from Mylan, Janssen-Ortho, Otsuka and Lundbeck. He has research contracts with Boehringer-Ingelheim, Lundbeck, and Otsuka-Lundbeck. He received advisor fees from Otsuka-Lundbeck, Janssen-Ortho, and AbbVie. He received speaker fees from Otsuka-Lundbeck, Janssen-Ortho, and Mylan.

Funding

The study and medical writing were sponsored by Lundbeck Canada Inc. and Otsuka Canada Pharmaceutical Inc.

Author’s contributions

OO, GC, WJ, FT and MAR conceptualized and designed the study. Collection and analysis of data was done by an independent clinical research organization. Data were interpreted by all authors.

Acknowledgements

We would like to thank the people who take care of the coffee machines in our respective offices. Without them, this work would have hardly been possible. We would like to thank Tanja Burkard (Anfomed GmbH) for performing the statistical analyses and Philipp Bauknecht (Dr. Carl GmbH) for writing services on behalf of Lundbeck Canada Inc. and Otsuka Canada Pharmaceutical Inc. We also thank the investigators and participants of the two original studies.

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Competing interest reported. The study and medical writing were sponsored by Lundbeck Canada Inc. and Otsuka Canada Pharmaceutical Inc.

OO has worked as a consultant, advisor and presented for Purdue, Sunovion, Pfizer, AbbVie/Allergan, Janssen Pharm., HLS Pharm., and Otsuka/Lundbeck Alliance. GC was an employee of Lundbeck Canada Inc. at the time of writing. WJ is an employee of Lundbeck GmbH. DS received honoraria for lectures from, or has been an advisor to, Janssen GmbH, Lundbeck GmbH, Otsuka Pharma GmbH, Rovi and Takeda. FT is an employee of Otsuka Canada Pharmaceutical Inc. KW received honoraria for lectures and advisory board participation from Janssen-Cilag GmbH, Lundbeck GmbH and Otsuka GmbH. MAR received investigator research grants from Mylan, Janssen-Ortho, Otsuka and Lundbeck. He has research contracts with Boehringer-Ingelheim, Lundbeck, and Otsuka-Lundbeck. He received advisor fees from Otsuka-Lundbeck, Janssen-Ortho, and AbbVie. He received speaker fees from Otsuka-Lundbeck, Janssen-Ortho, and Mylan.

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Improvement of functioning in patients with schizophrenia: Real-world effectiveness of aripiprazole once-monthly (REACT study)

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Abstract

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Background

Methods

Results

Total population

Patients ≤35 years and >35 years

Patient gender

Disease duration

Baseline severity

Responders

Composite responders

Functional remission

Discussion

Limitations

Conclusion

Abbreviations

Declarations

References

Additional Declarations

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