Discussion
In this multicentre trial of males with ASD, 4 weeks of treatment with multiple doses of TTA-121 revealed a peak of efficacy at 6 U with inverted U-shape as the dose–response relationship of intranasal oxytocin. The ASD social core symptoms were improved during the TTA-121 6 U-administered period compared with the placebo period in the PPS.
The inverted U-shape dose–response relationship of oxytocin is consistent with previous studies in experimental animals[26] and single administrations in healthy humans.[23–25] In rabbit brains, as TTA-121 has a 3.0 times higher maximum plasma concentration (Cmax) and 3.6 times higher AUCt compared with Syntocinon®,[28] based on the assumption that the results from rabbit approximates those from human, the peak dose of TTA-121 6 U approximately corresponds to Syntocinon® 18 to 21.6 U per day, which is lower than the doses in previous studies of repeated oxytocin administration in adults with ASD (i.e. 32 U[11] or 48 U[9,17,34]). The current findings suggest that suboptimal doses of oxytocin may contribute to the inconsistent efficacies of previous studies with repeated administration.
Although there were significant improvements in the PPS, no significant effects were observed in the FAS. Most dropouts from FAS to PPS were because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). It is therefore reasonable to detect significant efficacy in the PPS, without subjects with poor adherence who were included in the FAS. However, because FAS is considered as the sample closest to general clinical situations,[50] future studies with a larger sample size should show the efficacy of TTA-121 in FAS. Considering the robust preclinical data on the social effect of oxytocin in animal models,[51] the lack of robust effects in clinically relevant outcomes in the FAS in the current study may have been related to the context in which the intervention was given. It has been proposed that oxytocin is most effective when combined with specific contexts[52] or with other compounds.[53,54] For example, it has been suggested that intranasal oxytocin might be effective for enhancing the efficacy of behavioural therapies, because animal studies suggest that oxytocin enhances the salience of social cues and therefore could make behavioural therapy more salient and effective.[55] Future studies should examine this issue with a combination of intranasal oxytocin and behavioural therapies.
No secondary outcome results supported the efficacy of TTA-121 that was revealed for the primary outcome, although some exploratory outcomes results supported this efficacy. The differences between the current study and previous studies showing significant improvements of oxytocin on these secondary outcomes[19,34] have several possible causes. First, our previous study with a parallel-group design demonstrated that quantified facial expression and eye gaze were advantageous for controlling the placebo effect compared with ADOS,[19,34] whereas the current crossover-design trial showed an adequately suppressed placebo effect with ADOS. Therefore, although the detectability of ADOS showed some advantages in the crossover trial, the advantages of quantified social behaviours can be expected in a future parallel-group trial rather than a crossover trial. Second, our previous study included longitudinal assessments every 2 weeks showed time-course changes in efficacy as assessed by quantified facial expressions (such as the maximum improvement at 2 weeks and deterioration at 4 and 6 weeks).[19,54] The current study only used 0- and 4-week assessments and therefore cannot rule out the possibility of improvements at 2 weeks. Future studies should address this possibility.
Limitations
First, the current early-phase trial should be verified in a future large trial. The effect size of TTA-121 6 U on ADOS reciprocity in the FAS (i.e. d = 0.384) indicates that the sample size should be larger (i.e. n = 56 with sufficient power 0.8) to detect the significant effects of TTA-121 on ADOS reciprocity in FAS. Although the current crossover design appears to control the placebo effect, the efficacy of TTA-121 should be verified in a future parallel-group trial. Second, the current early-phase study was confined to Japanese men with high-functioning ASD. Although such homogeneous characteristics enhance the detection of TTA-121 efficacy, the generalizability of current findings regarding the efficacy and safety of TTA-121 should be tested in future trials. Third, considering the exploratory nature of the current study, correction for multiple testing was not used to identify the dose–response relationship among multiple candidate contrasts. A future verification study is also needed to determine the dose–response relationship.
Brain. 2022;145(2):490-499. © 2022 Oxford University Press
