Table 1.

Clinical efficacy and safety.

Author (Year)	Groups Studied and Intervention	Results and Findings	Conclusions
Turncliff R. et al. (2014) [85]	A phase 1, randomized, open-label, single-dose study. 46 patients were randomized to two groups; 441 mg IM injection administered at deltoid site or 441 mg IM injection at gluteal site. Maximum plasma concentration (Cmax) and area under the plasma concentration time curve from time zero to infinity (AUC0–inf) of aripiprazole and its metabolite dehydro-aripiprazole were measured. AEs were measured as tolerability outcomes	Deltoid administration resulted in higher Cmax aripiprazole concentration, while AUC0–inf was similar for both sites. Dehydro-aripiprazole exposure was 33% and 36% of aripiprazole exposure for deltoid and gluteal administration, respectively. The most common AE was injection site pain, with a higher incidence in the deltoid group.	Deltoid and gluteal injection sites provided similar levels of exposure and were both well-tolerated in patients with chronic stable schizophrenia.
Meltzer H. et al. (2015) [87]	A phase 3, randomized, double-blind, placebo-controlled trial. 623 patients (ages 18–70) experiencing an acute exacerbation of schizophrenia were randomized 2:2:1:1 to AL 441 mg, AL 882 mg, placebo low volume, and placebo high volume, respectively. Injections were administered in the gluteal muscle on days 1, 29 and 57. The primary efficacy endpoint was change from baseline to day 85 in PANSS total score, and the secondary efficacy endpoint was CGI-I score at day 85.	Placebo-adjusted least squares mean differences of PANSS total score were significantly lower for both AL 441 mg and AL 882 mg; p < 0.001 for both. CGI-I scores for both AL groups were also significantly better than placebo (Wilcoxon rank sum test: p < 0.001).	Both doses of AL were highly efficacious in treating an acute exacerbation of schizophrenia, with a safety and tolerability profile similar to oral aripiprazole, therefore representing a new treatment option.
Nasrallah H. et al. (2016) [94]	Patients with schizophrenia were randomly assigned to AL 441 mg, AL 882 mg, or placebo intramuscularly. Body weight, body mass index, fasting blood glucose and serum lipids, glycosylated hemoglobin (HbA1c), and prolactin were the parameters evaluated for 12 weeks. Treatment-emergent adverse events (AEs) were used for safety evaluations.	For both AL groups compared with placebo, mean body weight increased slightly and prolactin levels decreased, while changes in lipid parameters (total cholesterol, LDL cholesterol and triglycerides), plasma glucose, and HbA1c were insignificant. The incidence of AEs related to metabolic parameters was low.	Both AL 441 mg and AL 882 mg showed a small weight gain compared with placebo but otherwise reflected a low-risk metabolic profile.
Citrome L. et al. (2016) [95]	Patients with schizophrenia were randomly assigned to AL 441 mg, AL 882 mg, or placebo intramuscularly. Study endpoints were PANSS Hostility item (P7) score in the subpopulation of patients with a PANSS Hostility item P7 score of more than 1 at baseline, PSP disturbing and aggressive behavior domain and PANSS excited component (PANSS-EC) score.	AL groups compared with placebo resulted in significant lowering in proportion with PANSS Hostility item P7 more than 1 at endpoint (p < 0.05), as well as significant improvement (p < 0.05) in PANSS excited component score. The proportion of patients with aggressive behavior on the Personal and Social Performance scale was also significantly lower for both 441 mg and 882 mg compared with placebo (p = 0.006 and p < 0.001, respectively).	AL treatment displayed efficacy in reducing agitation and hostility in patients with schizophrenia.
Nasrallah H. et al. (2017) [88]	Phase 3, international, 52-week, open-label extension study with 478 patients. 368 received AL 882 mg and 110 received AL 441 mg as their fixed-dose regimen. Of the 478, 236 entered from a phase 3 study and 242 entered as outpatients with no prior AL exposure and a Clinical Global Impression–Severity score of ≤3 [mild] at screening. Metabolic parameters of weight, fasting blood sugar, lipids and serum prolactin were assessed for changes	The mean changes from baseline in the overall population were +1.1 mg/dL for glucose, +0.07 for glycated hemoglobin (HbAlc), −3.3 mg/dL for total cholesterol, and −5.3 mg/dL for triglycerides, while prolactin change from baseline was −8.7 ng/mL (14.7) for men and −14.9 (43.4) ng/mL for women. The retention rates at 6 months and 1 year were 86% and 68%, respectively.	Long-term AL treatment lead to slight lowering of serum with insubstantial changes in other assessed parameters.
Potkin S. et al. (2017) [90]	Patients with schizophrenia were randomly assigned to AL 441 mg, AL 882 mg, or placebo intramuscularly. Post-hoc analysis of the patient subgroup with severe psychotic symptoms (PANSS total score greater than the median score of 92). Primary outcome measured was mean change from baseline to day 85 in PANSS Total score. Categorical responder rate (defined as ≥30% improvement in PANSS Total score or a final CGI-I score of ≤2 [very much or much improved]) was also evaluated.	Both AL 441 mg and 882 mg demonstrated statistically significant and clinically meaningful improvements in PANSS Total score, with placebo-adjusted differences of −14.7 (p < 0.0001) and −16.6 (p < 0.0001), respectively, as well as significant findings with responder rates (p < 0.001) for both groups vs. placebo. Moreover, AL-882 mg resulted in a higher responder rate.	Both doses of AL demonstrated robust efficacy in treating patients with severe psychotic symptoms. The 882 mg dose displayed a numerically greater improvement in symptoms and proportion of responders.
Targum S. et al. (2017) [91]	Patients with schizophrenia were randomly assigned AL 441 mg, AL 882 mg, or placebo intramuscularly. Post-hoc gender and age analysis of AL treatment response, with age groups <30, 30–39, 40–49, and 50–69 years old. The primary outcome measured was change in total PANSS score from baseline to day 85. Categorical treatment response (defined as ≥30% total PANSS score improvement from baseline) was also measured.	ANCOVA analysis of change in PANSS score showed no significant interaction effects between age and treatment for both AL 441 mg versus placebo and AL 882 mg versus placebo; (F = 0.27; p = 0.60) and (F = 0.92; p = 0.34), respectively. The odds ratios (ORs) for treatment response rates showed higher association for either AL dose versus placebo for all age groups. No interaction effect between gender and treatment was observed, with outcomes for both men and women being better in AL groups than placebo.	AL 441 mg and AL 882 mg led to significant improvement in mean total PANSS score and categorical treatment response compared with placebo, regardless of patient age and gender.
McEvoy J. et al. (2017) [96]	Post-hoc analysis of long-term outcomes in patients who had completed both a phase 3 and extension study. Outcomes measured were rates of retention and remission, as well as treatment response trajectories, as measured by PANSS total and CGI-S item scores in AL 441 mg and AL 882 mg groups.	A statistically significant decrease occurred for PANSS total score (p < 0.0001 for both groups) and CGI-S scores ((p < 0.0001 for both groups). By week 64, remission rates were 73.8% and 68.1% in the 441 mg and 882 mg groups, respectively, with the median remission time from the beginning of the 12 weeks being 16.1 and 16.4 weeks, respectively. Retention rates were 72.8% and 66.0% for the 441 mg and 882 mg groups, respectively.	Both Al 441 mg and AL 882 mg exhibited continued therapeutic benefit in the long-term, as evidenced by high retention rates and significant improvements in clinical symptoms.
Miller B. et al. (2019) [89]	A phase 4, 6-month, prospective, open-label study in which 51 patients switched from either PP or RLAI to AL. Outcomes measured were CGI-S scores, BPRS scores, all-cause and medication-related discontinuation and adverse events. AEs were also assessed.	CGI-S and BPRS scores showed significant improvement, and the retention rate with all-cause and medication-related discontinuation rates at the end of 6 months was 30% and 9%, respectively. The retention rate at the end of 6 months was 68.6%, while the incidence of AEs was 41.2%, with the most frequent psychotic disorder, anxiety and schizophrenia.	Patients being treated with PP or RLAI who experience continued symptoms or tolerability issues can switch to AL, as the latter is well-tolerated.
Correll C. et al. (2019) [92]	Patients with schizophrenia were randomly assigned to AL 441 mg, AL 882 mg, or placebo intramuscularly. Post-hoc social and functional outcomes analysis of 596 of the total 623 patients. Outcomes measured were 6-item PANSS Prosocial subscale, 4-item PANSS Prosocial subscale and Personal and Social Performance (PSP) total score.	Both 6- and 4-item PANSS Prosocial Scores showed significant improvement for both doses of AL versus placebo, with the treatment effect sizes for PANSS Prosocial scores with AL 441 mg versus placebo being Cohen’s d=0.52 and AL 882 mg versus placebo being Cohen’s d=0.49. There was a significant increase in PSP total score for both doses versus placebo, with treatment effect sizes of Cohen’s d = 0.51 and 0.59 for AL 441-mg or AL 882-mg compared with placebo, respectively.	Treatment with AL 441 mg and AL 882 mg compared with placebo produces significant improvements in social functioning.
Citrome L. et al. (2019) [93]	Patients with schizophrenia were randomly assigned to AL 441 mg, AL 882 mg, or placebo intramuscularly. Post-hoc analysis with categorical efficacy and tolerability. Outcomes measured were number needed to treat (NNT) for therapeutic outcomes, number needed to harm (NNH) for adverse outcomes, and likelihood to be helped or harmed (LHH).	For pooled doses of AL, an NNT of 6 (95% CI: 5–11) was calculated when the response threshold was ≥30% improvement from baseline PANSS total score. For discontinuation due to AEs, a NNH estimate of −8 (95% CI: −6 to −15) for the pooled doses of AL vs placebo was calculated, while for Akathisia, the NNH was 14 (95% CI: 9–33). LHH value, using the NNT for response (≥30% reduction from baseline in PANSS total score) and the NNH for akathisia, was 2.3.	Aripiprazole lauroxil is efficacious and well-tolerated in the treatment of an acute exacerbation of schizophrenia, as evidenced by NNT and NNH values.
Peters L. et al. (2019) [97]	A systematic review of 31 RCTs (7 primary studies and 24 post hoc analyses) to evaluate comparisons of LAIs to placebo, OAPs or another LAI and 5 meta-analyses of RCTs comparing LAI to OAPs, all published 2016–2019. AL was among the LAIs analyzed.	LAIs were vastly superior to placebo and partly superior to OAPs for prevention of relapse and hospitalization and were comparable to OAPs for all-cause discontinuation, functioning, quality of life, and tolerability, as well as being associated with higher patient satisfaction and service engagement. Results from recent meta-analyses did not show an advantage for OAPs over LAIs.	Results from RCTs show that LAIs outperform placebo but are better than OAPs in only some aspects. Meta-analyses results do not reveal an advantage for OAP vs. placebo.
Weiden P. et al. (2020) [86]	A phase I, open-label, multicenter study, with 105 patients randomized to one of three AL dose regimens of 1064-mg injections every 8 weeks, 882-mg injections every 6 weeks, or 441-mg injections every 4 weeks, for a total of 24 weeks, with a 20-week follow-up. Plasma aripiprazole concentrations and AEs were evaluated.	Both 1064-mg and 882-mg regimens provided comparable aripiprazole exposure, higher than that of 441-mg. Most AEs were mild or moderate, with injection-site pain being the most frequent AE in all three regimens. Discontinuation due to TEAEs was 2.9%, 11.8% and 5.7% in the 1064-mg, 882-mg and 441-mg groups, respectively.	All three dosing regimens provide continuous exposure to AL, including 1064-mg administered every 2 months, and all produced a safety profile similar to previously established safety profiles.