Role of sublingual asenapine in treatment of schizophrenia

Figures & data

Table 1 Acute schizophrenia randomized controlled trials testing potentially therapeutic doses of asenapine (dosed twice daily) for which results are available*

Clinicaltrials.gov Identifier (if available) and manufacturer identifier (s)	Duration (weeks)	Randomized (n)	Asenapine dose (n)	Active control dose (n)	Placebo (n)	Comments
041004 (4)	6	182	5 mg bid (60)	Risperidone 6 mg/day (60)	62	Mean baseline total PANSS score 92–96. Discontinuation rates were 54% for asenapine, 58% for risperidone, and 66% for placebo. Asenapine 10 mg/day statistically separated from placebo on the primary outcome measure (PANSS total) but the active control did not. At study end or last observation, mean improvements on PANSS total, negative subscale, and general psychopathology subscale scores were all significantly greater with asenapine than with placebo (P < 0.005, P = 0.01, and P < 0.005, respectively). Compared with placebo, improvements on CGI-S and PANSS positive subscale scores were significantly greater with both asenapine (P < 0.01 and P = 0.01) and risperidone (P < 0.005 and P < 0.05).
NCT00156117, 41021, Hera (26)	6	417	5 mg bid (106); 10 mg bid (102)	Olanzapine 15 mg/day (103)	106	Mean baseline total PANSS score 91–94. Discontinuation rates were 42% for asenapine 5 mg bid, 50% for asenapine 10 mg bid, 43% for olanzapine and 50% for placebo. None of the asenapine dose levels statistically separated from placebo on the primary outcome measure (PANSS total) but the active control did.
NCT00151424, 41022, Hera (26)	6	277	5 or 10 mg bid (91)	Olanzapine 10–20 mg/day (93)	93	Mean baseline total PANSS score 85–87. Discontinuation rates were 53% for asenapine, 53% for olanzapine and 48% for placebo. None of the asenapine dose levels statistically separated from placebo on the primary outcome measure (PANSS total). The active control also failed to statistically separate from placebo.
NCT00156104, 41023, Hera (3)	6	458	5 mg bid (114); 20 mg bid (106)	Haloperidol 8 mg/day (115)	123	Mean baseline total PANSS score 88–89. Discontinuation rates were 37% for asenapine 5 mg bid, 33% for asenapine 10 mg bid, 41% for haloperidol and 43% for placebo. Asenapine 10 mg/day, but not 20 mg/day, statistically separated from placebo on the primary outcome measure (LOCF, PANSS total). The active control statistically also separated from placebo. However, using MMRM, PANSS changes at day 42 were significantly greater with asenapine at 10 and 20 mg/day and haloperidol than placebo (P < 0.05). On the PANSS positive subscale, all treatments were superior to placebo with LOCF and MMRM; asenapine 10 mg/day was superior to placebo on the negative subscale with MMRM and on the general psychopathology subscale with LOCF and MMRM.
NCT00281320, A7501021, P05717 (23)	6	122	2, 5, then 10 mg bid (61), 5 then 10 mg bid (61)	NA	NA	This was a safety, tolerability and pharmacokinetic study conducted in older patients. Tolerability was comparable for both titration schedules tested. Compared with younger patients, drug exposure was 12%–30% higher.
A7501001 (8, 9)	16 days	148	5 then 10 mg bid (38), 15 then 20 mg bid (38)	Quetiapine 375 mg bid (37)	35	This study focused on the ECG QT interval.

Note:

* Study results for NCT01101464 (24) are available on clinicaltrials.gov but omitted from this table because this was a pharmacokinetic study and although randomized, was open-label, included only eightr subjects, and lasted less than one week.

Abbreviations: bid, twice daily; CGI-S, Clinical Global Impressions-Severity; ECG, electrocardiogram; LOCF, last observation carried forward; MMRM, mixed model for repeated measures; NA, not applicable; PANSS, Positive and Negative Syndrome Scale.

Table 2 Longer-term randomized controlled trials of asenapine for schizophrenia for which results are available

Clinicaltrials.gov Identifier (if available) and manufacturer’s identifier (s)	Duration (weeks)	Randomized (n)	Asenapine dose (n)	Comparator or active control dose (n)	Placebo (n)	Comments
NCT00212784, 25517, ACTAMESA (6)	52	1225	5 or 10 mg bid (913)	Olanzapine 10–20 mg/day (312)	NA	Mean baseline total PANSS score was 92. The primary outcome measure was change in the PANSS total score. Among all randomized patients, PANSS total score improved with both agents but the improvement was greater with olanzapine than with asenapine. Asenapine was associated with less weight gain than olanzapine but with more frequent extrapyramidal symptoms.
NCT00212771, 25520, P05846, ACTAMESA (13, 14)	104	440	5 or 10 mg bid (290)	Olanzapine 10–20 mg/day (150)	NA	Extension study for above. Efficacy was largely maintained. Incidence of weight gain of at least 7% from baseline was 28% for asenapine and 40% for olanzapine.
NCT00150176, A7501012 (5, 19)	26	386	5 or 10 mg bid (194)	NA	192	Mean baseline total PANSS score was 54 for asenapine and 53 for placebo. The primary outcome measure was time to relapse/impending relapse. This is the maintenance of response/relapse prevention study that was used to gain FDA approval for the maintenance treatment of schizophrenia.
NCT00156065, 41513, Hera (12, 20)	52	187	5 or 10 mg bid (93)	Haloperidol 2–8 mg bid (43)	51 placed on asenapine from placebo	This was an extension to the acute study that utilized haloperidol as an active control.^Citation3 Extrapyramidal symptoms were more common with haloperidol.
NCT00145496, A7501013, Aphrodite, P05771 (18)	26	468	5 or 10 mg bid (244)	Olanzapine 5–20 mg/day (224)	NA	The focus of this study was for patients with persistent negative symptoms. No statistically significant differences were found between groups on negative symptom scores or quality of life scores.
NCT00174265, A7501014, Aphrodite, P05772 (9, 21)	26	196	5 or 10 mg bid (86)	Olanzapine 5–20 mg/day (110)	NA	Extension to the above study. Asenapine was superior to olanzapine on negative symptom scores. No statistically significant difference on quality of life scores.
NCT00265343, 25544, Aphrodite (22)	26	306	5 or 10 mg bid (134)	Olanzapine 5–20 mg/day (172)	NA	This is an extension to a study for patients with persistent negative symptoms. The parent study results are not available. Limited results for the extension are available from clinicaltrials.gov.^Citation22 No statistically significant differences were found between groups on negative symptom scores.^Citation16

Abbreviations: bid, twice daily; NA, not applicable; PANSS, Positive and Negative Syndrome Scale.

Figure 1 Number needed to treat.³⁵

Table 3 Commonly encountered (incidence ≥5% and two-fold greater than placebo for at least one of the doses) spontaneously reported adverse events as reported in product labeling for the acute treatment of schizophrenia: percentage of patients reporting reaction and number needed to harm versus placebo*

Adverse event	Asenapine studies
	Placebo	Asenapine 10 mg/day		Asenapine 20 mg/day
	Rate	Rate	NNH	Rate	NNH
Somnolence	7%	15%	13	13%	17
Akathisia	3%	4%	100	11%	13
Oral hypoesthesia	1%	6%	20	7%	17

Notes:

* Data from Table 2 in product labeling for asenapine.²

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