Post-acute Infectious Syndrome - Aripiprazole Symptom Evaluation (PAIS-AriSE)

Background: Post-acute infectious syndrome (PAIS) describes persistent health problems that develop after an acute infection and continue for at least three months. The condition includes post-COVID-19 condition (PCC or Long COVID) but may also occur after other viral or bacterial infections. Common symptoms include severe fatigue, problems with memory and concentration ("brain fog"), post-exertional malaise (worsening of symptoms after physical or mental activity), sleep disturbances, mood changes, and reduced physical functioning. These symptoms can substantially impair daily activities, work, education, and quality of life. Although the number of affected individuals has increased considerably in recent years, there are currently no approved pharmacological treatments specifically targeting the neuropsychiatric symptoms of PAIS. Management is largely limited to supportive care and symptom-based treatment. There is therefore a substantial need for safe and effective therapies.

Study Rationale: Aripiprazole is an atypical antipsychotic that has been approved for many years to treat psychiatric disorders such as schizophrenia and bipolar disorder. At considerably lower doses than those used in psychiatry, aripiprazole has pharmacological effects that may influence dopamine signaling, neuroinflammation, and immune regulation, mechanisms that have been proposed to contribute to the development and persistence of symptoms in PAIS. Preliminary observational studies have suggested that low-dose aripiprazole may improve fatigue, cognitive symptoms, and overall functioning in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition that shares many clinical features with PAIS. However, these findings have not yet been confirmed in randomized controlled clinical trials. The PAIS-AriSE study has been designed to evaluate the efficacy and safety of low-dose aripiprazole using a rigorous randomized, double-blind, placebo-controlled study design.

Study Objectives: The primary objective is to determine whether treatment with low-dose aripiprazole results in greater improvement in fatigue than placebo after the first 8-week treatment period.

Secondary objectives include evaluating the effects of treatment on:

* fatigue in participants fulfilling diagnostic criteria for ME/CFS; * fatigue severity and physical functioning; * health-related quality of life; * memory performance and other cognitive functions; * mood; * post-exertional malaise; * illness-related anxiety and distress; and * the safety and tolerability of low-dose aripiprazole.

Study Design: PAIS-AriSE is a prospective, randomized, double-blind, placebo-controlled, phase 2b crossover trial. Approximately 138 adults with neuropsychiatric symptoms associated with PAIS will be enrolled to ensure that at least 120 participants complete at least one follow-up assessment.

Following screening and baseline assessments, eligible participants will be randomly assigned in a 1:1 ratio to one of two treatment sequences. Randomization will be stratified by age and sex assigned at birth.

Participants assigned to Sequence A will receive oral low-dose aripiprazole for 8 weeks, followed by a 2-week washout period and then 8 weeks of placebo.

Participants assigned to Sequence B will receive placebo for 8 weeks, followed by the same washout period and then 8 weeks of low-dose aripiprazole.

Study medication and placebo capsules will be identical in appearance. Participants, investigators, and study personnel involved in study conduct and outcome assessment will remain unaware of treatment allocation throughout the study.

Study Assessments: Participants will undergo screening and baseline assessments before treatment begins. During the study, fatigue, physical functioning, quality of life, memory, cognitive performance, mood, post-exertional malaise, and illness-related anxiety and distress will be evaluated using validated patient-reported outcome measures and neuropsychological assessments. Follow-up visits will take place after each treatment period.

The primary efficacy endpoint is the change in fatigue after the first treatment period, measured using the Chalder Fatigue Questionnaire (CFQ). Additional validated questionnaires and neuropsychological assessments will be used to evaluate secondary outcomes.

Safety: Safety will be monitored throughout the study by recording adverse events, serious adverse events, and suspected unexpected serious adverse reactions. The safety profile of low-dose aripiprazole in this patient population will be evaluated alongside its potential clinical benefits.

Expected Significance: The PAIS-AriSE trial is designed to provide high-quality evidence on whether low-dose aripiprazole can safely improve fatigue and other neuropsychiatric symptoms in people with PAIS. If successful, the study could identify a readily available oral treatment for a condition with limited therapeutic options and contribute to improving the care of individuals living with persistent symptoms after infection.

• Intra-patient change in CFQ by ≥3 points from baseline to week 9 in the subgroup fulfilling ME/CFS criteria. [Time frame: 9 weeks after first IMP intake]
• Intra-patient change in CFQ from baseline to week 19 and from week 9 to week 19. [Time frame: 9 and 19 weeks after first IMP intake]
• Intra-patient change in the Fatigue Severity Score (FSS) from baseline to week 9 and to week 19 and from week 9 to week 19. [Time frame: 9 and 19 weeks after first IMP intake]
• Intra-patient change in the Bell Disability Scale from baseline to week 9 and to week 19 and from week 9 to week 19 [Time frame: 9 and 19 weeks after first IMP intake]
• Intra-patient change in the PROMIS-29 questionnaire from baseline to week 9 and to week 19 and from week 9 to week 19. [Time frame: 9 and 19 weeks after first IMP intake]
• Intra-patient change in the Short Form 36 Health Survey - Physical Functioning (SF-36 PF) from baseline to week 9 and to week 19 and from week 9 to week 19 [Time frame: 9 and 19 weeks after first IMP intake]
• Intra-patient change in the Multifactorial Memory Questionnaire (MMQ) subscale memory satisfaction from baseline to week 9 and to week 19 and from week 9 to week 19 [Time frame: 9 and 19 weeks after first IMP intake]
• Intra-patient change in the Becks Depression Inventory (BDI-II) from baseline to week 9 and to week 19 and from week 9 to week 19 [Time frame: 9 and 19 weeks after first IMP intake]
• Intra-patient change in the Post Exertional Malaise (PEM) questionnaire from baseline to week 9 and to week 19 and from week 9 to week 19 [Time frame: 9 and 19 weeks after first IMP intake]
• Intra-patient change in the Somatic Symptom Disorder-B Criteria Scale (SSD-12) from baseline to week 9 and to week 19 and from week 9 to week 19 [Time frame: 9 and 19 weeks after first IMP intake]
• Difference in the occurrence of Adverse Events (AE) and Serious Adverse Events (SAE) between Aripiprazole and Placebo (IMP safety). [Time frame: 9 and 19 weeks after first IMP intake]