Prednisone in Adults With an Immune-Mediated Subtype of Autism Spectrum Disorder

Randomized, Double-Blind, Placebo-Controlled, Parallel-Groups Trial of Prednisone in Adults With an Immune-Mediated Subtype of Autism Spectrum Disorder

The goal of this clinical trial is to learn how prednisone affects adults with autism spectrum disorder (ASD). It will also learn about the safety of prednisone. The main questions it aims to answer are:

• How does prednisone affect the core features and associated target symptoms of ASD in adults with an immune-mediated subtype of ASD?
• Is prednisone safe for autistic adults without causing too many side effects?
• Does this study warrant larger trials studying anti-inflammatory drugs in this subject population?

Researchers will compare the drug prednisone to a placebo (a look-alike substance that contains no drug) to see how prednisone affects autistic adult males.

Participants will:

• Visit the clinic 2 times for a screening and baseline visit.
• Take prednisone or a placebo every day for 16 weeks.
• Visit the clinic 2 times for checkups, tests, questionnaires, and dose changes, and 1 time for a follow-up visit 4 weeks after stopping the study drug.
• Provide blood and urine samples for testing up to 4 times.
• Complete 8 remote calls every 1-2 weeks for checkups and dose changes.
• Keep a diary of the dose and times they take the study drug every day and any symptoms or side effects they experience.

• Randomized, double-blind, placebo-controlled, parallel-groups, flexibly dosed trial. Eligible autistic male participants will be randomized 1:1 to receive prednisone or a placebo.
• Participants will attend up to 5 in-person study visits: screening, baseline, Week 5, Week 10, and Week 20 (post-discontinuation follow-up).
• Interim dose adjustments will be determined during 8 scheduled remote visits: Weeks 1-4, Week 7, Week 12, Week 14, and Week 16.
• Blood and urine specimens will be collected for safety and biomarker assessments: screening, Week 5, Week 10, and Week 20.

Inclusion Criteria:

1. 18 to 50 years of age (inclusive) and assigned male at birth.

2. Diagnostic Statistical Manual of Mental Disorders (DSM), Fourth Edition, Text Revision (DSM-IV-TR) diagnosed autistic disorder, and DSM, Fifth Edition, Text Revision (DSM-5-TR) diagnosed autism spectrum disorder (ASD), level 2 or 3. A qualified (board-eligible or board-certified) psychiatrist or psychologist, with experience in diagnostic determinations of ASD, will make a final diagnostic determination based on clinical history, clinical observations, medical records, mental status exams, and screening measures.

3. A Clinical Global Impression-Severity (CGI-S) rating ≥ 4 ("Moderate") at screening (and baseline).

4. A non-verbal IQ in the range of moderate intellectual disability or higher (≥ 35), as measured by the non-verbal Abbreviated IQ (ABIQ) score of the Stanford-Binet Intelligence Scales, Fifth Edition (SB-5), or mental age of at least 18 months, as measured by the Cognitive and Adaptive Behavior subscales of the Developmental Profile (DP-4) Parent/Caregiver Interview form.

5. Participation of a study partner who has consistent contact with the participant and is willing and able to attend visits, oversee the participant's compliance with the protocol and study medication, and report on the participant's status through study assessments.

6. Participant reports ≥ 1 of the following:

   • A diagnosed comorbid autoimmune disease (e.g., Crohn's disease, Graves' disease, Hashimoto's disease, psoriasis, rheumatoid arthritis, ulcerative colitis, type 1 diabetes mellitus, etc.).
   • Current biomarker evidence of critical indicators of inflammation/autoimmunity, such as elevated levels of C-reactive protein (CRP) or abnormal value of antinuclear antibodies (ANA).
   • A significant family history of autoimmunity, defined as having ≥ 1 first-degree relative or ≥ 2 second-degree relatives with autoimmune diseases. The Principal Investigator (PI) will make the final determination on this criterion.

7. Any concomitant medications or interventions for ASD-related symptoms (e.g., alpha-2 agonists, anticonvulsants, antidepressants, antipsychotics, anxiolytics, gastrointestinal medications, medications for sleep disorders, probiotics, stimulants, behavioral therapies, psychosocial interventions, speech therapy, etc.) have been stable for at least 4 weeks prior to the screening visit and the participant/study partner intend to maintain a stable regimen throughout the trial.

8. Participant can tolerate swallowing large capsules.

9. Participant is willing and able, in the investigator's opinion, to comply with all study procedures.

Individuals must satisfy the following criteria to be enrolled as study partners:

1. The study partner is fluent in English.
2. The study partner is a caregiver or an individual who has consistent contact with the participant, knows the participant well, and is willing and able to attend visits, oversee the participant's compliance with the protocol and study medication, and report on the participant's status through study assessments. The PI will make the final determination on this criterion.

Exclusion Criteria:

1. DSM-5-TR diagnosed ASD, level 1, or presence of another DSM-IV-TR diagnosed pervasive developmental disorder, such as Asperger's disorder, childhood disintegrative disorder, Rett syndrome, or pervasive developmental disorder not otherwise specified (PDD-NOS). A qualified psychiatrist or psychologist will make a diagnostic determination after reviewing clinical history, clinical observations, medical records, mental status exams, and screening measures.
2. A CGI-S rating < 4 at screening (or baseline).
3. A non-verbal IQ in the range of severe or profound intellectual disability (< 35), as measured by the non-verbal ABIQ score of the SB-5, or mental age below 18 months, as measured by the Cognitive and Adaptive Behavior subscales of the DP-4 Parent/Caregiver Interview form. Individuals testing below 18 months may be enrolled after a case review by the PI and study psychologist, especially if testing scores were likely underestimated due to uncooperative behavior.
4. Previous documentation of a prolonged electroencephalogram (EEG) suggestive of Landau-Kleffner syndrome or continuous spike and wave during sleep (CSWS) syndrome.
5. Presence of a defined genetic disorder, such as Angelman syndrome, Fragile X syndrome, Noonan syndrome, Tuberous sclerosis, Williams syndrome, or any documented chromosomal or genetic abnormality with proven clinical significance in the etiology of ASD.
6. Documented significant pre- or post-natal central nervous system insult, such as an in-utero cerebral vascular accident, that is believed to have significantly contributed to the development of the individual's ASD.
7. Mitochondrial disorder verified by skin and/or muscle biopsy.
8. History of bipolar disorder, psychotic disorder or schizophrenia.
9. History of one or more psychiatric hospitalizations due to symptoms of a major psychiatric disorder (e.g., major depressive disorder, OCD, PTSD, severe anxiety disorders, or substance use disorder). Hospitalization exclusively for irritability or behavioral dysregulation related to ASD, without evidence of a comorbid major psychiatric disorder, is permitted.
10. Concomitant medications or interventions for ASD-related symptoms (e.g., alpha-2 agonists, anticonvulsants, antidepressants, antipsychotics, anxiolytics, gastrointestinal medications, medications for sleep disorders, probiotics, stimulants, behavioral therapies, psychosocial interventions, speech therapy, etc.) have not been stable for at least 4 weeks prior to the screening visit.
11. An active bacterial, fungal, helminthic, protozoan, or viral infection that could be exacerbated by a course of prednisone, as determined by the PI.
12. Significant medical findings from history, physical examination, or laboratory testing that may be incompatible with prednisone use (e.g., participants with chronic infectious conditions or unstable diabetes mellitus, defined as insulin-dependent or HbA1c >7.0).
13. Individuals with a history of seizures being treated with an anticonvulsant may be eligible if seizure-free for at least 6 months and the anticonvulsant dose has been stable for at least 4 weeks prior to the screening visit.
14. Use of immunosuppressive agents within the 6 months prior to the screening visit or concurrent use of immunosuppressive agents that, in the judgment of the PI, would interfere with study outcomes or pose unreasonable risk with prednisone administration.
15. A known hypersensitivity to prednisone or any other component of the study product.
16. The participant is deemed unsuitable for any reason by the PI, including an inability to complete or comply with study requirements.

Individuals may be excluded from enrollment as study partners if either of the following criteria are met:

1. The study partner is not fluent in English.
2. The study partner is deemed unsuitable for any reason by the PI, including an inability to complete or comply with study requirements.