But trial may not close the book on this intervention

Daily intranasal oxytocin therapy for 24 weeks did not improve social skills in children and adolescents with autism spectrum disorder, the SOARS-B trial found.

No significant differences emerged in the least-squares mean change from baseline on measures of social or cognitive functioning between pediatric patients treated with oxytocin versus placebo, reported Linmarie Sikich, MD, of Duke University in Durham, North Carolina, and co-authors in The New England Journal of Medicine.

“There was a great deal of hope this drug would be effective,” Sikich said in a statement. “All of us on the study team were hugely disappointed, but oxytocin does not appear to change social function of people with autism.”

Participants included in the primary outcome efficacy analysis were randomized to oxytocin (n=139) or placebo (n=138). They completed baseline and additional assessments that included the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW, which ranges from 0 to 39 with higher scores indicating less social interaction).

Over the 24-week course of the study, the least-squared mean change in the score was −3.7 points in the oxytocin group and −3.5 for placebo (mean difference 0.2, 95% CI −1.5 to 1.0; P=0.61).

“The absence of between-group differences in outcomes was similar among participants with fluent verbal communication and among those with minimal verbal communication, and the results for the secondary outcomes were generally similar to that for the primary outcome,” Sikich and co-authors wrote.

The group conducted the trial from August 2014 through June 2017, recruiting English-speaking guardians and patients ages 3-17 who met DSM-5 criteria for autism spectrum disorder but had not been diagnosed with Rett syndrome, childhood disintegrative disorder, deafness, blindness, active cardiovascular or renal disease, or uncontrolled epilepsy. Patients were stratified as minimally verbal versus fluently verbal.

Study assessments were done at baseline and every 4 weeks to 24 weeks. The oxytocin dose began at 8 IU with a target daily dose of 48 IU generally achieved at week 8 and given as 24 IU twice daily. Dosing was flexible and could be decreased or maintained based on requests from physician, caregiver, or participant. Dose increases before the suggested time on the schedule were not permitted.

Most participants included in the efficacy analysis (87%) were male. Minimal verbal fluency was seen in 48% overall, while 52% had fluent verbal speech. One-quarter (25%) of participants were ages 3-5, 39% were ages 7-11, and 36% were ages 12-17. The median ABC-mSW score at baseline was 11, and the mean maximal total daily dose was about 68 IU in the oxytocin group.

Three secondary outcomes—none significantly different for oxytocin versus placebo groups—included a measure of social motivation, a social function score, and a score of cognitive abilities.

Safety analysis showed any adverse event in 82% of the oxytocin and 83% of the placebo group, with rates for the oxytocin and placebo groups, respectively, of increased appetite (16% versus 10%), increased energy (10% versus 3%), increased restlessness 8% versus 2%), subjective weight loss (7% versus 3%), increased thirst (6% versus 3%), inattention (6% versus 3%), and myalgia (3% versus 1%).

“The three secondary outcomes essentially affirmed the absence of a difference between the trial groups,” the researchers noted. “The incidence and severity of adverse events were similar in the two groups.”

“What can we conclude from this well-powered, carefully conducted trial?” wrote Daniel Geschwind, MD, PhD, of the University of California Los Angeles, in an accompanying editorial.

“First, we see that oxytocin as administered in previous clinical studies and trials and in a method similar to most off-label use in clinical practice did not improve social function in a generalizable population of persons with autism spectrum disorder,” Geschwind noted. “These results do not support the current off-label use of oxytocin in the treatment of autism spectrum disorder.”

“Nevertheless, it may be premature to summarily reject the oxytocin signaling pathway (or efforts to increase social motivation in general) as a potential treatment target in autism spectrum disorder,” he stated.

Factors to consider when interpreting the trial’s results include the age range of the persons, and Geschwind noted: The physiologic effects of oxytocin differ over developmental stages and there may be critical windows for treatment. A likely short half-life of oxytocin activity in the brain also may limit the effectiveness of even sustained twice-daily administration, he pointed out. In addition, standard measures of social motivation are insensitive, he noted.

“Clinical efficacy may require drug administration that is temporally coupled with behavioral intervention,” Geschwind observed.

A decade of interest in oxytocin’s behavioral effects has led to significant research interest in its use for addressing core symptoms of autism.

“Many children with autism spectrum disorder are thought to have tried intranasal oxytocin therapy on the basis of putatively promising data,” Sikich and co-authors wrote. This treatment approach has been driven by trials of a single dose of oxytocin or by small studies, they noted.

A 2020 trial studied 106 adults with autism spectrum disorder ages 18-48 who received 6-week intranasal oxytocin versus placebo. No between-group difference was seen on a primary outcome of social reciprocity, but a secondary outcome favored the intervention on a measure of repetitive behavior. The investigators also noted that baseline-to-endpoint plasma oxytocin level was elevated in the oxytocin, but not placebo group.

In the SOARS-B trial, sensitivity analysis controlling for baseline oxytocin level did not appreciably change results.

Limitations of SOARS-B include its use of the ABC-mSW, a non-validated measure for primary outcome. “In the absence of trials showing a replicable benefit of any intervention for social functioning in persons with autism spectrum disorder, it is difficult to know which outcome measure is most appropriate to assess potential social improvement in future trials,” Sikich and colleagues wrote.

The study’s flexible dosing strategy also differed from oxytocin dosing protocols used in previous clinical trials.

  1. Daily intranasal oxytocin therapy for 24 weeks did not improve social skills in children and adolescents with autism spectrum disorder, the SOARS-B trial found.

  2. Results do not support the current off-label use of oxytocin to treat autism spectrum disorder.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This study was funded by the National Institute of Child Health and Human Development.

Sikich reported work with F. Hoffmann-La Roche Ltd., and is exploring a patent on a formulation of intranasal oxytocin used in the study.

Geschwind reported relationships with AcuraStem, Axial Biotherapeutics, Ovid Therapetics, F. Hoffmann-La Roche Ltd., and Takeda Pharmaceutical Company, outside the submitted work.

Cat ID: 128

Topic ID: 82,128,730,128,135,192,925