Effect of a Novel Nasal Oxytocin Spray With Enhanced Bioavailability on Autism: A Randomized Trial

A Randomized Trial

Hidenori Yamasue; Masaki Kojima; Hitoshi Kuwabara; Miho Kuroda; Kaori Matsumoto; Chieko Kanai; Naoko Inada; Keiho Owada; Keiko Ochi; Nobutaka Ono; Seico Benner; Tomoyasu Wakuda; Yosuke Kameno; Jun Inoue; Taeko Harada; Kenji Tsuchiya; Kazuo Umemura; Aya Yamauchi; Nanayo Ogawa; Itaru Kushima; Norio Ozaki; Satoshi Suyama; Takuya Saito; Yukari Uemura; Junko Hamada; Yukiko Kano; Nami Honda; Saya Kikuchi; Moe Seto; Hiroaki Tomita; Noriko Miyoshi; Megumi Matsumoto; Yuko Kawaguchi; Koji Kanai; Manabu Ikeda; Itta Nakamura; Shuichi Isomura; Yoji Hirano; Toshiaki Onitsuka; Hirotaka Kosaka; Takashi Okada

Disclosures

Brain. 2022;145(2):490-499.

Conclusions

The current multicentre trial investigated 4 weeks of treatment with a wide range of doses of TTA-121, a novel oxytocin nasal spray with enhanced bioavailability, and revealed an inverted U-shape dose–response relationship with a peak at a dose lower than that expected from previous studies in subjects with ASD. The ASD social core symptoms were significantly improved with the TTA-121 6 U compared with placebo in the PPS. Although the current trial supports the efficacy of TTA-121 on ASD core symptoms and its safety, improvement did not reach statistical significance in the FAS. Thus, the efficacy should be verified in a future large-scale, parallel-group trial.

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Abbreviations
ADOS = Autism Diagnostic Observation Schedule; ASD = autism spectrum disorder; FAS = full analysis set; PPS = per protocol set

Acknowledgements
The corresponding author had full access to the data and held the final responsibility regarding the decision to submit for publication. We acknowledge the invaluable contributions of Ms Yumi Kiyama in the recruitment and screening processes. We thank Bronwen Gardner, PhD, from Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript.

Funding
This research was supported by Japan Agency for Medical Research and Development (AMED) under Grant Number JP19lk0201071, JP20lk0201116, and JP16dm0107134.

Competing interest
There are no conflicts of interest. The investigational drugs in this clinical trial, including TTA-121 and placebo, were provided by Teijin Pharma Limited. Neither the funder nor sponsor had any involvement in the data collection, analyses, writing, or interpretation of the study.

Table 1. Characteristics of each administration group at baseline (safety analysis set)
Characteristics	Placebo (total) n = 103	Oxytocin 3 U n = 25	Oxytocin 6 U n = 28	Oxytocin 10 U n = 27	Oxytocin 20 U n = 25
Age, mean (SD), years	28.3 (8.4)	29.1 (7.7)	28.0 (8.8)	29.0 (9.2)	28.0 (8.2)
Height, cm	170.6 (5.4)	171.5 (5.3)	170.4 (6.5)	171.6 (5.0)	169.2 (5.0)
Body weight, kg	68.2 (14.6)	71.7 (15.8)	68.3 (14.0)	67.9 (14.1)	67.1 (13.9)
Self SES: 1/2/3/4/5	8/37/20/25/13	3/10/7/1/4	1/8/4/7/8	1/13/1/10/2	3/7/8/7/0
Parental SES: 1/2/3/4/5	12/54/29/8/0	3/17/4/1/0	4/11/9/4/0	2/13/11/1/0	2/15/6/2/0
Autism Diagnostic Interview-Revised
Social	19.9 (5.4)	21.2 (5.0)	19.3 (5.4)	18.9 (5.6)	20.2 (5.4)
Communication	14.2 (4.4)	15.2 (3.5)	13.7 (4.3)	13.7 (4.8)	14.3 (4.9)
Repetitive	5.4 (2.7)	5.8 (3.1)	5.5 (2.8)	4.6 (2.5)	5.6 (2.7)
Wechsler Adult Intelligent Scale-III
Full IQ	107.5 (14.3)	109.5 (14.1)	107.0 (15.1)	108.3 (14.1)	104.8 (13.8)
Verbal IQ	111.7 (15.6)	113.8 (18.2)	111.0 (12.0)	113.7 (15.4)	110.4 (13.1)
Performance IQ	97.8 (18.1)	97.3 (16.7)	100.4 (20.0)	99.0 (14.6)	96.0 (17.9)
Current psychotropic medications	29/103	3/25	9/28	9/27	8/25

IQ = intelligence quotient; SES = socioeconomic status, where a lower value indicates a higher socioeconomic status.

Table 2. Dose–response relationships for the primary outcome: ADOS reciprocity
Contrasts [Placebo, 3 U, 6 U, 10 U, 20 U]	P-value*
Contrasts [Placebo, 3 U, 6 U, 10 U, 20 U]	FAS	PPS
Linear dose−response relationship [2,1,0, −1, −2]	0.599	0.984
Peak at 10 U/morning [9, 4, −1, −6, −6]	0.705	0.710
Peak at 10 U/morning with inverted U-shape [8,3, −2, −7, −2]	0.922	0.378
Peak at 3 U/morning and evening [7, 2, −3, −3, −3]	0.799	0.292
Peak at 3 U/morning and evening with inverted U-shape_1 [4, −1, −6, −1, 4]	0.182**	0.073**
Peak at 3 U/morning and evening with inverted U-shape_2 [1, 0, −1, 0, 0]	0.193	0.082
Peak at 3 U/morning [4, −1, −1, −1, −1]	0.915	0.408
Peak at 3 U/morning with inverted U-shape [1, −1, 0, 0, 0]	0.650	0.983

*P-values calculated from analyses performed by applying the mixed-effects model with the amount of change in each administration period as the response variable, with the content of administration (placebo, 3 U, 6 U, 1 0U, 20 U) and the order of administration (active drug→placebo/placebo→active drug) as the fixed effects, with the interaction between the content of administration and the order of administration, and with the effect of the individual as a random effect.
**P-values showing the minimum value.

Table 3. Observed changes from baseline to end point for the primary outcome: ADOS reciprocity
Dose	Administration	n	Baseline	End point	Change	Mean difference	95% CI	P-value	Cohen's d
FAS
6 U*
	6 U	25	8.2 (3.4)	7.7 (3.1)	−0.5 (1.3)	−0.5	−1.1 to 0.1	0.118	−0.384
	Placebo (6 U)	24	7.7 (3.3)	7.5 (3.3)	−0.1 (1.3)
3 U
	3 U	25	7.1 (2.4)	7.1 (2.7)	0.0 (1.8)	0.3	−0.5 to 1.2	0.389	0.333
	Placebo (3 U)	23	7.4 (2.4)	6.9 (2.7)	−0.5 (0.9)
10 U
	10 U	26	7.2 (3.0)	7.3 (2.6)	0.1 (1.5)	0.0	−0.8 to 0.8	1.000	0.000
	Placebo (10 U)	27	7.4 (2.4)	7.4 (2.6)	0.0 (1.2)
20 U
	20 U	24	8.1 (2.0)	8.2 (2.9)	0.1 (1.4)	0.0	−0.8 to 0.8	1.000	0.000
	Placebo (20 U)	23	7.9 (2.3)	8.2 (2.2)	0.3 (1.3)
PPS
6 U*
	6 U	22	8.4 (3.6)	7.9 (3.3)	−0.5 (1.3)	−0.8	−1.3 to −0.2	0.012*	−0.667
	Placebo (6 U)	20	7.9 (3.4)	8.1 (3.3)	0.2 (1.2)
3 U
	3U	22	7.2 (2.5)	7.1 (2.9)	−0.1 (1.8)	0.4	−0.5 to 1.3	0.384	0.444
	Placebo (3 U)	21	7.4 (2.5)	6.9 (2.8)	−0.6 (0.9)
10 U
	10 U	22	7.8 (2.6)	7.6 (2.6)	−0.2 (1.4)	−0.4	−1.2 to 0.4	0.358	−0.333
	Placebo (10 U)	23	7.8 (2.3)	7.9 (2.3)	0.1 (1.2)
20 U
	20 U	23	8.1 (2.1)	8.3 (2.9)	0.1 (1.5)	0.0	−0.8 to 0.9	0.909	0.000
	Placebo (20 U)	22	8.0 (2.4)	8.2 (2.2)	0.2 (1.3)

Baseline, end point and change data are presented as mean (SD).
*The dose of contrast showing the smallest P-value for the dose–response relationship.
**P < 0.05 from paired t-tests.

Authors and Disclosures

Hidenori Yamasue^1,2, Masaki Kojima³, Hitoshi Kuwabara^1,2, Miho Kuroda⁴, Kaori Matsumoto⁵, Chieko Kanai⁶, Naoko Inada⁴, Keiho Owada⁷, Keiko Ochi⁸, Nobutaka Ono⁹, Seico Benner¹, Tomoyasu Wakuda¹, Yosuke Kameno¹, Jun Inoue¹⁰, Taeko Harada², Kenji Tsuchiya², Kazuo Umemura¹¹, Aya Yamauchi¹², Nanayo Ogawa¹³, Itaru Kushima¹³, Norio Ozaki¹³, Satoshi Suyama¹⁴, Takuya Saito¹⁴, Yukari Uemura¹⁵, Junko Hamada³, Yukiko Kano³, Nami Honda¹⁶, Saya Kikuchi¹⁶, Moe Seto¹⁶, Hiroaki Tomita¹⁶, Noriko Miyoshi¹⁷, Megumi Matsumoto¹⁷, Yuko Kawaguchi¹⁷, Koji Kanai¹⁷, Manabu Ikeda¹⁷, Itta Nakamura¹⁸, Shuichi Isomura¹⁸, Yoji Hirano¹⁸, Toshiaki Onitsuka¹⁸, Hirotaka Kosaka¹⁹ and Takashi Okada¹³

1 Department of Psychiatry, Hamamatsu University School of Medicine, 1–20-1 Handayama, Higashiku, Hamamatsu City 431–3192, Japan
2 Department of Child Development, United Graduate School of Child Development at Hamamatsu, 1–20-1 Handayama, Higashiku, Hamamatsu 431–3192, Japan
3 Department of Child Neuropsychiatry, School of Medicine, The University of Tokyo, 7–3-1 Hongo, Bunkyo-ku, Tokyo 113–8655, Japan
4 Department of Psychology, Faculty of Liberal Arts, Teikyo University, Tokyo, Japan
5 Graduate School of Psychology, Kanazawa Institute of Technology, 7–1 Ohgigaoka, Nonoichi 921–8054, Japan
6 Child Development and Education, Faculty of Humanities, Wayo Women's University, Konodai 2–3-1, Ichikawa, Chiba 272–0827, Japan
7 Department of Pediatrics, School of Medicine, The University of Tokyo, 7–3-1 Hongo, Bunkyo-ku, Tokyo 113–8655, Japan
8 School of Media Science, Tokyo University of Technology, Hachioji, Japan
9 Department of Computer Science, Graduate School of Systems Design, Tokyo Metropolitan University, Hino, Japan
10 Department of Child and Adolescent Psychiatry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashiku, Hamamatsu City 431–3192, Japan
11 Department of Pharmacology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashiku, Hamamatsu City 431–3192, Japan
12 Department of Medical Technique, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466–8560, Japan
13 Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466–8550, Japan
14 Department of Child and Adolescent Psychiatry, Hokkaido University Hospital, Sapporo, Japan
15 Biostatistics Section, Department of Data Science, Center for Clinical Science, National Center for Global Health and Medicine, Shinjyu-ku, Tokyo 162–8655, Japan
16 Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Japan
17 Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan
18 Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
19 Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui 910–1193, Japan

Correspondence to
H. Yamasue Department of Psychiatry, Hamamatsu University School of Medicine 1-20-1 Handayama, Higashiku, Hamamatsu City 431–3192, Japan E-mail: yamasue@hama-med.ac.jp