Transcranial Pulse Stimulation (TPS) in Post-COVID-19

Study Overview
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Brief Summary
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The objective of the present study is to demonstrate treatment efficacy of transcranial pulse stimulation for patients with Post-COVID-19 related neurological symptoms (fatigue, cognitive deficits, mood deterioration). Fatigue, as measured by the Fatigue Impact Scale (FIS), will represent the primary outcome variable. The verum treatment will be compared to a sham (placebo) condition.

Detailed Description
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This clinical trial aims to investigate the treatment efficacy of transcranial pulse stimulation (TPS) using the NEUROLITH device (Storz Medical AG, Tägerwilen, Switzerland) in individuals with neurological post-COVID-19-symptoms. The study employs a double-blind, randomized, placebo-controlled [multicenter-]* design with parallel groups (verum vs. sham). The anticipated timeframe for the entire study is 2 years, during which each participant is expected to be actively engaged for a period of 3-4 months. The aim is to include [120] patients, with 90 individuals participating in the Austrian center [and 30 in the Italian center]. The randomization ratio is 1:1, ensuring an even distribution between the verum (active treatment) and sham (placebo) groups. Three assessment points are scheduled (Baseline, PostStim, 1monthPostStim). Furthermore, to determine potential effects over time, limited data collection (involving only FIS, BDI-II, and SF-36) is planned at later time points, specifically at 3 months post-stimulation and 6 months post-stimulation (only at the Austrian center). Hypotheses H0: There is no significant difference in the effectiveness of transcranial pulse stimulation (TPS) and placebo treatment in improving primary and secondary endpoints. H1: There is a significant difference in the effectiveness of transcranial pulse stimulation (TPS) and placebo treatment in improving primary and secondary endpoints. Timeline Each study participant will undergo the following sequence: Initial information session and clarification of relevant medical findings regarding inclusion and exclusion criteria Baseline screening: 3-4 assessment sessions per patient within 14 days, including informed consent Patients who do not meet the predefined cut-off values for BDI, FIS, and MoCA will be excluded from subsequent study phases Transcranial pulse stimulation 5 stimulations per patient within 10 days One stimulation per day lasting approximately 30 minutes. Post-stimulation assessment (PostStim) Conducted during the week following brain stimulation 2-3 assessment sessions per patient within 7 days One-month post-stimulation assessment (1monthPostStim) Conducted one month after brain stimulation 2-3 assessment sessions per patient within 7 days Deviations of + 5 days from the intended timeline are considered tolerable. Sample Size Calculation The sample size calculation conducted with G*Power incorporated a small effect size (f = .10), α error probability of .05, and a power of 0.8, resulting in an estimate of 102 patients. While the consideration of a 12.5% drop-out rate from a previous study (Beisteiner et al., 2019) would yield a sample size of 114.75, a more conservative approach is being employed: To ensure sufficient participant numbers, the aim is to enroll 120 patients. [Italian Center Adaptation: The Italian center will use the Austrian center as a template while considering available resources, potentially leading to a reduced number of data collection instruments and sessions per assessment point. After obtaining approval, this passage will be revised to include relevant information for the Italian center.] [...]* indicates aspects of the planned multicenter design. The center in Italy is currently undergoing the approval process. Updates to this page will be made once confirmations are obtained.

Official Title
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Transcranial Pulse Stimulation (TPS) in Post-COVID-19

Conditions
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Post-COVID-19 Syndrome, Fatigue

Intervention / Treatment
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* Device: Transcranial pulse stimulation Verum
* Device: Transcranial pulse stimulation Sham


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent PCR-confirmed SARS-CoV-2 infection At least 12 months after initial SARS-CoV-2 infection that led to Post-COVID (subsequent SARS-CoV-2 infections are not a reason for exclusion) Diagnosis of Post-COVID Syndrome or independent suspected diagnosis of Post-COVID Syndrome (Considering that physicians generally hesitate to provide clear-cut Post-COVID diagnoses, a tentative diagnosis by an independent general practitioner or a specialist in a field associated with Post-COVID will suffice for entering this study) Age: 20-80 Evidence of a negative pregnancy test if medically adequate Exclusion Criteria: Clinically relevant realization of pre-COVID diseases with similar symptoms as Post-COVID MoCA score <17 (cut-off for dementia) BDI-II score ≥29 (cut-off for severe depression) FIS <10 (cut-off for no fatigue) Brain implants Non-MR-compatible metal parts in the body Metal parts in the head Use of anticoagulants Non-MR-compatible claustrophobia Non-MR-compatible pacemaker Pregnant and breastfeeding women Clinically relevant history of surgery on the head, heart, or vessels Corticosteroid treatments administered within 6 weeks prior to the first application Cancer, tumor Blood clotting disorders Participation in other studies

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, [multicenter], double-blind, randomized, parallel group, placebo-controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Verum TPS<br>Participants will receive 5 Verum TPS sessions over a period of 10 days, with a singular daily session, each lasting approximately 30 minutes | Device: Transcranial pulse stimulation Verum<br>* Participants are slated to undergo a total of five TPS sessions over a 10-day interval. Each stimulation session will endure approximately 30 minutes and will be administered once daily.<br>|
| Sham Comparator: Sham TPS<br>Participants will receive 5 Sham TPS sessions over a period of 10 days, with a singular daily session, each lasting approximately 30 minutes | Device: Transcranial pulse stimulation Sham<br>* Placebo treatment will be performed using the same medical device, handpiece and treatment paradigm as in the verum treatment with one difference: the standoff device at the end of the handpiece. This device is designed to replicate the appearance, feel, and sound of the verum system, while omitting the transmission of any pulses.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fatigue Impact Scale (FIS) | The Fatigue Impact Scale (Fisk et al., 1994) is an instrument to measure the impact of fatigue symptoms. This self-report measure consists of 40 items divided into three subscales: cognitive functioning (10 items), physical functioning (10 items) and psychosocial functioning (20 items). In the validated German version, the statements are scored from 0-4 (0=never, 4=very often) leading to a total score of 0-160. | Baseline - 1 week after stimulation - 1 month after stimulation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Beck Depression Inventory (BDI-II) | The Beck Depression Inventory (BDI-II) is one of the most widely used instruments for measuring the severity of depression. It is a 21-item questionnaire for self-evaluation with 0-3 scores per item, ranging from 0 (normal state) to 63 (severe depression). | Baseline - 1 week after stimulation - 1 month after stimulation | 
| Montreal Cognitive Assessment (MOCA) | Montreal Cognitive Assessment (Nasreddine et al., 2005) is a clinical standard test for evaluating the following cognitive functions: visuospatial/executive, naming, memory, attention, language, abstraction, recall and orientation. The maximum score is 30 points. | Baseline - 1 week after stimulation - 1 month after stimulation | 
| 36-Item Short Form Health Survey (SF-36) | The 36-item short-form health survey (Ware et al., 1992) is a widely used instrument to measure quality of life. The 36-item patient-reported survey covers eight health concepts including physical functioning (10 items), role limitations due to physical health (4 items), role limitations due to emotional problems (3 items), energy/fatigue (4 items), emotional well-being (5 items), social functioning (2 items), pain (2 items), and general health (5 items). All questions are scored on a scale from 0 (worst health) to 100 (best health). | Baseline - 1 week after stimulation - 1 month after stimulation | 
| Trail Making Test A and B (TMT-A and TMT-B) | The Trail Making Test (Reitan et al., 1958) consist of two parts A and B. For each part, patients need to fulfill a task by connecting letters and/or numbers in the right way. The scoring of both parts is done by taking the time required to complete them. | Baseline - 1 week after stimulation - 1 month after stimulation | 
| Positive and Negative Affect Schedule (PANAS) | The Positive and Negative Affect Schedule (Watson et al., 1988) is an instrument to assess mood, specifically distinguishing between positive and negative affect. It has two subscales (positive and negative) and consists out of 20 items which are scored using a 5-point scale (1= not at all - 5 = extremely). | Baseline - 1 week after stimulation - 1 month after stimulation | 
| Beck Anxiety Inventory (BAI) | The Beck Anxiety Inventory (Beck et al., 1988) is a self-reported scale to measure anxiety. It consists of 21 items, which are scored from 0-3. The BAI has a total range from 0 to 63. | Baseline - 1 week after stimulation - 1 month after stimulation | 
| Six Minute Walking Test (6MWT) | The six-minute walking test, developed by the American Thoracic Society 2002, is an exercise test to assess aerobic capacity and endurance. The patients are asked to walk as far as they can within 6 minutes. Subjective tests (Borg-Scale, 0-10) will be administers before and after walking. | Baseline - 1 week after stimulation - 1 month after stimulation | 
| Test of Attentional Performance (TAP) | The Test of Attentional Performance (Zimmermann et al., 2002) is an instrument to measure attentional function. There are 14 subscales, including Sustained Attention, Vigilance, and Divided Attention. It will be carried out digitally using the TAP software package. | Baseline - 1 week after stimulation - 1 month after stimulation | 
| Verbal Learning and Memory Test (VLMT) | The German version of the Verbal Learning Memory Test by Helmstaedter and colleagues (2001) is an instrument to measure different parameters of declarative verbal memory such as learning or recognition performance. It consists of a learning phase, in which patients need to learn two lists of 15 words each, a delayed recall and a recognition test. | Baseline - 1 week after stimulation - 1 month after stimulation | 
| Stroop color word test (STROOP) | The Stroop Color-Word Test (Stroop, 1935) is a useful and reliable psychological assessment tool (Lezak, Howieson, & Loring, 2004) that measures a person's ability to inhibit an automatic response in favor of an atypical one. Specifically, it involves identifying the ink color of incongruously labeled color words (van Boxtel et al., 2001). The test can measure cognitive performance functions such as naming speed, selectivity, and alertness (Bäumler & Stroop, 1985). | Baseline - 1 week after stimulation - 1 month after stimulation | 
| Satisfaction With Life Scale (SWLS) | The SWLS (Satisfaction with Life Scale), developed by Diener and colleagues (1985), is a widely used self-report questionnaire designed to measure individuals' subjective satisfaction with their own lives. It consists of five items that capture different aspects of life satisfaction. | Baseline - 1 week after stimulation - 1 month after stimulation | 
| Somatization subscale of the Symptom Check List-90-R (SCL-90-R SOM) | The SCL-90-R (Schmitz et al., 2000) is a 90-item self-report symptom inventory used in clinical and research settings to evaluate psychological symptoms and distress. Only the SOM (Somatization) subscale within the SCL-90-R will be used for the present study. It consists of 12 items on a 5-point Likert scale that assess physical symptoms. The maximum score for the subscale is 48 points. | Baseline - 1 week after stimulation - 1 month after stimulation | 
| Post-Exertional Malaise (BI-PEM) | The German version of the DSQ PEM questionnaire (Cotler et al., 2018; Jason & Sunnquist, 2018) comprises three subscales and a total of 11 items, focusing on post-exertional malaise. The subscales include questions concerning frequency, severity and duration of the symptoms after engaging in activities over the past 6 months. | Baseline - 1 week after stimulation - 1 month after stimulation | 
| Neuroimaging | Magnetic resonance imaging (MRI) will be recorded the week before, the week after and 1 month after TPS stimulations by center 1 (Vienna) for the Austrian study population. MR measurements will be performed using a 3 T SIEMENS PRISMA MR with a 64-channel head coil. MRI images will be obtained to assess changes in structural and functional brain connectivity. | Baseline - 1 week after stimulation - 1 month after stimulation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transcranial Pulse Stimulation, Post-COVID-19, Fatigue, Non-invasive brain stimulation