Post-acute infectious syndrome (PAIS), including post-COVID-19 condition (PCC or Long COVID), can develop after an infection and may cause persistent symptoms such as fatigue, problems with memory and concentration ("brain fog"), mood changes, and reduced quality of life. In some people, these symptoms continue for months or longer and can substantially affect daily activities. Currently, there are no approved treatments that specifically target these symptoms. Aripiprazole is a medicine that is approved to treat certain psychiatric disorders. At low doses, it may affect brain signaling and immune processes that are thought to contribute to symptoms experienced by people with PAIS. Small observational studies have suggested that low-dose aripiprazole may improve symptoms such as fatigue and cognitive impairment in people with related conditions, but its effectiveness and safety have not yet been confirmed in a randomized controlled trial. The purpose of this study is to evaluate whether low-dose aripiprazole is safe and more effective than placebo in improving fatigue and other neuropsychiatric symptoms in adults with PAIS. This is a phase 2b, randomized, double-blind, placebo-controlled crossover trial. Approximately 138 participants with PAIS will be enrolled. Participants will be randomly assigned to one of two treatment sequences. One group will receive low-dose aripiprazole for 8 weeks followed by placebo for 8 weeks. The other group will receive placebo first, followed by low-dose aripiprazole. The two treatment periods will be separated by a 2-week washout period. Neither the participants nor the study team will know which treatment is being given during each treatment period. The primary objective is to determine whether low-dose aripiprazole improves fatigue after the first 8-week treatment period compared with placebo. Fatigue will be assessed using the Chalder Fatigue Questionnaire. Secondary objectives include evaluating the effects of treatment on physical functioning, quality of life, memory and cognitive performance, mood, post-exertional malaise, illness-related anxiety and distress, and fatigue in participants who meet diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Safety will be assessed throughout the study by monitoring adverse events. The results of this study may help determine whether low-dose aripiprazole is a safe and effective treatment option for people with PAIS
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
138
The treatment period consists of two consecutive 8-week periods of blinded IMP administration: 8 weeks of aripiprazole followed by 8 weeks of placebo (Sequence A), or 8 weeks of placebo followed by 8 weeks of aripiprazole (Sequence B). Follow-up assessments will be conducted after each treatment period, at Weeks 9 and 19 of the study.
The treatment period consists of two consecutive 8-week periods of blinded IMP administration: 8 weeks of active comparator followed by 8 weeks of placebo (Sequence A), or 8 weeks of placebo followed by 8 weeks of active comparator (Sequence B).
Charité - Universitätsmedizin Berlin
Berlin, State of Berlin, Germany
Intra-patient change in the Chalder Fatigue Scale (CFQ) by ≥ 3 points from baseline to week 9 in patients with PAIS.
The CFQ assesses the extent and severity of fatigue and has been used in multiple randomized controlled trials of behavioral interventions in patients with ME/CFS. Each of the 11 items is rated on a 4-point scale, resulting in a total score ranging from 0 (no symptoms) to 33 (maximum symptom severity). In this trial, intra-patient change in CFQ by ≥3 points from baseline to week 9 will be interpreted as meaningful improvement.
Time frame: 9 weeks after first IMP intake
Intra-patient change in CFQ by ≥3 points from baseline to week 9 in the subgroup fulfilling ME/CFS criteria.
@Studyteam: Please add a description of how the ME/CFS subgroup is defined in this trial.
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.
The within-patient change in physical and mental fatigue, as measured by the CFQ, will be assessed 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.
The FSS is a 9-item scale that assesses fatigue severity and its impact on a person's activities and lifestyle. Each item is rated on a 7-point scale (1 = strongly disagree; 7 = strongly agree), resulting in a total score ranging from 9 (no fatigue) to 63 (severe fatigue). The within-patient change in fatigue severity will be assessed from baseline to week 9, 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 Bell Disability Scale from baseline to week 9 and to week 19 and from week 9 to week 19
The Bell Disability Scale is a standard assessment tool used to evaluate functional ability in adults with ME/CFS. It comprises 11 statements describing the patient's functional status, including symptom severity at rest and during activity, overall activity level, and the ability to work, travel, and perform self-care activities. Scores range from 0 (bedridden) to 100 (no symptoms and fully functional). The within-patient change in functional ability will be assessed from baseline to week 9, 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 PROMIS-29 questionnaire from baseline to week 9 and to week 19 and from week 9 to week 19.
The PROMIS-29 is a patient-reported outcome measure that assesses physical, mental, and social health. It can be used in both the general population and individuals with chronic health conditions. The within-patient changes in the health domains assessed by the PROMIS-29 will be assessed from baseline to week 9, 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 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
The Short Form 36 Health Survey (SF-36) is an established and widely used measure of health-related quality of life. The Physical Functioning (PF) domain assesses limitations in ten activities related to mobility and self-care, such as walking specified distances, carrying groceries, bathing, and dressing. Scores are weighted and transformed to a scale ranging from 0 (severe functional limitations) to 100 (no functional limitations). The within-patient change in SF-36 PF will be assessed from baseline to week 9, 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 Multifactorial Memory Questionnaire (MMQ) subscale memory satisfaction from baseline to week 9 and to week 19 and from week 9 to week 19
The MMQ is a participant-reported outcome measure that assesses different aspects of subjective memory functioning. It comprises three subscales assessing memory satisfaction, perceived memory ability, and the use of memory strategies. The MMQ memory satisfaction subscale consists of 18 items rated on a 5-point Likert scale based on the participant's experiences during the previous two weeks. Scores range from 0 to 72, with higher scores indicating greater satisfaction with memory. A change of 13 points is considered clinically meaningful. The within-patient change in memory satisfaction will be assessed from baseline to week 9, 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 Becks Depression Inventory (BDI-II) from baseline to week 9 and to week 19 and from week 9 to week 19
The BDI-II is a widely used self-report questionnaire that assesses the severity of depressive symptoms in individuals aged 13 years and older. It consists of 21 items, each assessing a specific symptom of depression. Each item is rated on a scale from 0 to 3, with higher total scores indicating greater severity of depressive symptoms. The within-patient change in the severity of depressive symptoms will be assessed from baseline to week 9, 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 Post Exertional Malaise (PEM) questionnaire from baseline to week 9 and to week 19 and from week 9 to week 19
The PEM questionnaire assesses the frequency, severity, and duration of PEM. Frequency and severity scores each range from 0 to 20, with higher scores indicating more frequent and more severe PEM, respectively. Duration scores range from 0 to 6, with higher scores indicating longer-lasting PEM. The within-patient change in PEM frequency, severity, and duration will be assessed from baseline to week 9, 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 Somatic Symptom Disorder-B Criteria Scale (SSD-12) from baseline to week 9 and to week 19 and from week 9 to week 19
The SSD-12 is a 12-item self-report questionnaire that assesses the psychological features associated with somatic symptom disorder according to the DSM-5 B criteria. It assesses cognitive, affective, and behavioral responses to somatic symptoms, with four items covering each domain. Each item is rated on a 5-point scale from 0 to 4, resulting in a total score ranging from 0 to 48. Higher scores indicate greater psychological distress and symptom-related thoughts, feelings, and behaviors associated with somatic symptoms. The within-patient change in psychological responses to somatic symptoms will be assessed from baseline to week 9, from baseline 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).
The occurrence of adverse reactions and other safety events, including but not limited to infections, endocrine disorders, and psychiatric complications, will be assessed based on AE, SAE, and SUSAR reporting.
Time frame: 9 and 19 weeks after first IMP intake
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