Assessment of self-perceived stress and repetitive behaviors after six weeks of daily intranasal oxytocin administration versus placebo: a randomised, multicentre, parallel group pragmatic trial in 210 men and women with autism

Prior treatment

• Participant actively takes anti-epileptic medication or has a clinically significant and unstable medical condition. Conditions include hematological (e.g., severe anemia, clinically significant thrombocytopenia), endocrine (e.g., uncontrolled hypo-/hyperthyroidism, uncontrolled diabetes), cardiovascular (including any rhythm disorder; e.g., atrial fibrillation/flutter, supraventricular tachycardia, heart failure, uncontrolled hypertension), respiratory (e.g., moderate-to-severe COPD, severe or poorly controlled asthma), renal (e.g., moderate-to-severe chronic kidney disease, dialysis), hepatic (e.g., cirrhosis, active hepatitis), or gastrointestinal disease (e.g., malabsorption syndromes, major gastrointestinal surgery such as gastric bypass), ongoing oncological disorders, that may influence the metabolism of oxytocin (IMP). 2. Individuals with a severe intellectual disability are excluded from participation due to concerns regarding their capacity to provide independent informed consent, understand study procedures, self-administer the nasal spray, and complete self-report questionnaires. Individuals with a mild intellectual disability may be included, provided they are not under legal guardianship and demonstrate a literacy level at or above the equivalent of fourth grade in primary education. In the Belgian context, this corresponds to minimally having completed the 4th grade level in Special Education Primary School of type 9 or type 8 education in Flanders, or in type 8 education in Wallonia. 3. Participant has a known syndrome that interacts with the reproductive hormonal system (e.g. Prader-Willi or Angelman syndrome); 4. Participant who has had previous chronic treatment with oxytocin in the last 10 years; 5. Known hypersensitivity to active substance or ingredients in the nasal sprays, including e.g. (history of) latex allergy; 6. Use of any of the following medicinal products during the nasal spray administration period: - prostaglandins or their analogues - inhalation anesthetics - systemic vasoconstrictors or sympathomimetic agents - caudal anesthesia 7. Current participation in another interventional Trial with an investigational medicinal product (IMP) or device; 8. Individuals of childbearing potential will be excluded if they are pregnant (as determined by a urine pregnancy test at baseline [T0] prior to randomization), are breast-feeding, or intend to become pregnant during the nasal spray administration period. To minimize the risk of pregnancy, individuals of childbearing potential are required to use effective contraception or to abstain from vaginal intercourse for the duration of the nasal spray administration period. 9. Exposure to gender-affirming hormonal regimens or other high-dose or long-term exogenous sex hormone administrations (e.g., for gynecological disorders) resulting in substantial, sustained changes of endogenous sex hormone profiles constitutes an exclusion criterion, given current uncertainties regarding interactions with intranasal oxytocin and the potential impact on safety assessment and interpretability of study outcomes. Use of standard-dose oral contraceptives does not constitute an exclusion.

• Participants eligible for inclusion in this Trial must meet all of the following criteria: 1. Voluntary written informed consent of the participant has been obtained prior to any screening procedures 2. Must be at least 18 years of age at the time of signing the Informed Consent Form (ICF) 3. Diagnosis of Autism Spectrum Disorder (ASD) according to DSM-5 criteria OR Autistic Disorder (AD), Asperger Syndrome (AS) or Pervasive Developmental Disorder – Not Otherwise Specified (PDD-NOS) according to DSM-IV criteria, as established by a multidisciplinary team; 4. Participants are eligible if they self-report experiencing heightened stress for at least the past month. A formal questionnaire or cut-off score is not applied, allowing inclusion to be based on self-reported need and clinical judgment. All participants that are considered for Trial participation, per the above criteria will be documented via applicable log forms in Investigator Site File (including Screen Failures).