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.

Results

Baseline Characteristics

Before visiting each trial site, 34 of 210 candidates did not meet the eligibility criteria based on background information, 21 did not meet the criteria for Social Responsiveness Scale^[48] and/or Autism Spectrum Quotient^[49] scores (Supplementary material) and 11 declined to consent to participate. Of the 144 participants assessed for eligibility, consent was obtained from 127 adult males with ASD. Of these, 18 did not meet the eligibility criteria and 109 males with high-functioning ASD were enrolled between 25 June 2018 and 26 December 2019. End point assessments were performed between 27 September 2018 and 19 March 2020. The actual rate of withdrawal (7 of 109 cases, 6.4%) was lower than expected (i.e. 20%). Because the number of cases needed for analyses was calculated as ~120, we completed recruitment of 127 participants before registering a target sample size of 144 participants, which was calculated with an expected withdrawal rate of 20%.

Six of the 109 participants did not complete the trial because they withdrew their consent. Of these, three withdrew before the first administered period and three withdrew during the washout period. Another participant in the placebo-TTA-121 10 U group did not complete the trial because of an adverse event (a mild emergence of blasts in the blood) during the washout period (Figure 1).

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