Table 3.
Randomized controlled trials of inhaled loxapine – efficacy results
| Study | Outcomes | Loxapine versus placebo NNT (95% CI) for CGI-I response at 2 hours | Loxapine versus placebo NNT (95% CI) for PANSS-EC response at 2 hours | Loxapine versus placebo NNT (95% CI) for requiring only first dose by 24 hours and no rescue medication* | |||
|---|---|---|---|---|---|---|---|
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| 5 mg | 10 mg | 5 mg | 10 mg | 5 mg | 10 mg | ||
| Allen et al22 | Loxapine 10 mg, but not 5 mg, was superior to placebo on change in the PANSS-EC at 2 hours; mean 2 hour PANSS-EC scores were nine, eleven, and 13 for loxapine 10 mg, loxapine 5 mg, and placebo, respectively. The 5 mg dose effect size was intermediate between placebo and the 10 mg dose, suggesting a possible dose response relationship. The 10 mg dose separated from placebo as early as 20 minutes postdose, in contrast to the 5 mg dose which never separated from placebo to a statistically significant degree. Scores on the CGI-I scale at 2 hours after dose administration showed statistically significant effects of both the 10 mg (mean CGI-I 2.3) and 5 mg (mean CGI-I 2.6) loxapine dose versus placebo (mean CGI-I 3.2). BARS scores at 2 hours after inhalation demonstrated a statistically significant change from baseline for the 10 mg, but not the 5 mg dose group. Time to administration of first rescue medication (intramuscular lorazepam 0.5–2 mg) and overall use of rescue medication demonstrated advantages for both doses of inhaled loxapine versus placebo. Proportions of subjects receiving rescue medication were 15%, 11%, and 33% for those randomized to loxapine 10 mg, loxapine 5 mg, and placebo, respectively. | 4 (3–12) | 3 (2–5) | NA | NA | 5 (3–22) | 6 (NS) |
| Lesem et al23 | Both doses of loxapine, 5 and 10 mg, were superior to placebo on change in the PANSS-EC at 2 hours, with mean 2 hour PANSS-EC scores of approximately nine, ten, and twelve for loxapine 10 mg, loxapine 5 mg, and placebo, respectively. Both doses of loxapine demonstrated superiority to placebo as early as 10 minutes postinhalation. Scores on the CGI-I scale at 2 hours after dose administration showed statistically significant effects of both the 10 mg (mean CGI-I 2.1) and 5 mg (mean CGI-I 2.3) loxapine dose versus placebo (mean CGI-I 2.8). A Kaplan–Meier survival analysis of the time to a second dose of medication (if needed) demonstrated superiority of loxapine 10 mg over placebo, but not so for the 5 mg dose, suggesting a possible dose response. Proportions of subjects receiving rescue medication (intramuscular lorazepam, permitted after a second dose of randomized medication) were 5%, 6%, and 16% for those randomized to loxapine 10 mg, loxapine 5 mg, and placebo, respectively. Once randomized, no patient dropped out for failure to follow the inhalation instructions or an inability (or refusal) to take a dose of study drug. The ACES scores at 2 hours demonstrated that no patient had a score of nine (unarousable), and the mean ratings for the groups receiving inhaled loxapine were in the range of mild calmness (5 mg group: 4.7; 10 mg group: 4.9, where four = normal and five = mild calmness). | 5 (3–11) | 4 (3–6) | 5 (3–9) | 4 (3–6) | 12 (NS) | 7 (4–52) |
| Kwentus et al24 | Both doses of loxapine, 5 and 10 mg, were superior to placebo on change in the PANSS-EC at 2 hours, with mean 2 hour PANSS-EC scores of approximately eight, nine, and 13 for loxapine 10 mg, loxapine 5 mg, and placebo, respectively. Both doses of loxapine demonstrated superiority to placebo as early as 10 minutes postinhalation. Scores on the CGI-I scale at 2 hours after dose administration showed statistically significant effects of both the 10 mg (mean CGI-I 1.9) and 5 mg (mean CGI-I 2.1) loxapine dose versus placebo (mean CGI-I 3.0). Survival analysis of the time to a second dose of medication (if needed) demonstrated superiority of both loxapine 10 and 5 mg over placebo. Proportions of subjects receiving rescue medication (intramuscular lorazepam, permitted after a second dose of randomized medication) were 9%, 9%, and 21% for those randomized to loxapine 10 mg, loxapine 5 mg, and placebo, respectively. The ACES scores at 2 hours demonstrated that no patient had a score of nine (unarousable), and the mean ratings for the groups receiving inhaled loxapine were in the range of mild calmness (5 mg group: 4.7; 10 mg group: 5.1, where four = normal and five = mild calmness). | 3 (2–4) | 3 (2–3) | 3 (3–5) | 3 (2–3) | 7 (4–51) | 3 (3–5) |
Notes:
In contrast to the Phase III studies, the Phase II study did not include the possibility of a second dose of inhaled loxapine but did allow rescue medication with intramuscular lorazepam; additional NNT data from Citrome;29 CGI-I responders defined as subjects who have a CGI-I score of one (very much improved) or two (much improved) at 2 hours after inhalation; PANSS-EC responders defined as subjects who have a ≥40% reduction from baseline on the PANSS-EC at 2 hours after inhalation. Copyright © 2011. John Wiley and Sons. Adapted with permission from Blackwell Publishing Ltd. Citrome L. Aerosolised antipsychotic assuages agitation: inhaled loxapine for agitation associated with schizophrenia or bipolar disorder. Int J Clin Pract. 2011;65(3):330–340.28
Abbreviations: ACES, Agitation–Calmness Evaluation Scale; BARS, Behavioral Activity Rating Scale; CGI-I, Clinical Global Impressions – Improvement scale; CI, confidence interval; NA, not available; NNT, number needed to treat; NS, not significant; PANSS-EC, Positive and Negative Syndrome Scale – Excited Component.