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

Background: Post‐acute infectious syndrome (PAIS) describes persistent health problemsthat develop after an acute infection and continue for at least three months. Thecondition includes post‐COVID‐19 condition (PCC or Long COVID) but may also occur afterother viral or bacterial infections. Common symptoms include severe fatigue, problemswith memory and concentration ("brain fog"), post‐exertional malaise (worsening ofsymptoms after physical or mental activity), sleep disturbances, mood changes, andreduced physical functioning. These symptoms can substantially impair daily activities,work, education, and quality of life. Although the number of affected individuals hasincreased considerably in recent years, there are currently no approved pharmacologicaltreatments specifically targeting the neuropsychiatric symptoms of PAIS. Management islargely limited to supportive care and symptom‐based treatment. There is therefore asubstantial need for safe and effective therapies.Study Rationale: Aripiprazole is an atypical antipsychotic that has been approved formany years to treat psychiatric disorders such as schizophrenia and bipolar disorder. Atconsiderably lower doses than those used in psychiatry, aripiprazole has pharmacologicaleffects that may influence dopamine signaling, neuroinflammation, and immune regulation,mechanisms that have been proposed to contribute to the development and persistence ofsymptoms in PAIS. Preliminary observational studies have suggested that low‐dosearipiprazole may improve fatigue, cognitive symptoms, and overall functioning in patientswith myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition that sharesmany clinical features with PAIS. However, these findings have not yet been confirmed inrandomized controlled clinical trials. The PAIS‐AriSE study has been designed to evaluatethe 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‐dosearipiprazole results in greater improvement in fatigue than placebo after the first8‐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 symptomsassociated with PAIS will be enrolled to ensure that at least 120 participants completeat least one follow‐up assessment.Following screening and baseline assessments, eligible participants will be randomlyassigned in a 1:1 ratio to one of two treatment sequences. Randomization will bestratified 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 thesame 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 willremain unaware of treatment allocation throughout the study.Study Assessments: Participants will undergo screening and baseline assessments beforetreatment begins. During the study, fatigue, physical functioning, quality of life,memory, cognitive performance, mood, post‐exertional malaise, and illness‐related anxietyand distress will be evaluated using validated patient‐reported outcome measures andneuropsychological assessments. Follow‐up visits will take place after each treatmentperiod.The primary efficacy endpoint is the change in fatigue after the first treatment period,measured using the Chalder Fatigue Questionnaire (CFQ). Additional validatedquestionnaires and neuropsychological assessments will be used to evaluate secondaryoutcomes.Safety: Safety will be monitored throughout the study by recording adverse events,serious adverse events, and suspected unexpected serious adverse reactions. The safetyprofile of low‐dose aripiprazole in this patient population will be evaluated alongsideits potential clinical benefits.Expected Significance: The PAIS‐AriSE trial is designed to provide high‐quality evidenceon whether low‐dose aripiprazole can safely improve fatigue and other neuropsychiatricsymptoms in people with PAIS. If successful, the study could identify a readily availableoral treatment for a condition with limited therapeutic options and contribute toimproving the care of individuals living with persistent symptoms after infection.