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

Overview

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

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. TPS is a novel brain stimulation therapy based on non-invasive ultrasound pulses and first published in 2019 by the Medical University of Vienna, Austria (Beisteiner et al. Advanced Science, 2019). The study employs a double-blind, randomized, placebo-controlled 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 102 patients. 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, SF-36 and BI-PEM) is planned at later time points, specifically at 3 months post-stimulation, 6 months post-stimulation, 12 months post-stimulation, and 24 months post-stimulation.

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:

1. Initial information session and clarification of relevant medical findings regarding inclusion and exclusion criteria 2. 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 3. Transcranial pulse stimulation

* 5 stimulations per patient within 10 days * One stimulation per day lasting approximately 30 minutes. 4. Post-stimulation assessment (PostStim)

* Conducted during the week following brain stimulation * 2-3 assessment sessions per patient within 7 days 5. 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.

Important note: Originally, the study was designed as a multicenter study with the still-existing Austrian center (N=90) and an Italian center (N=30). Since study realization at the Italian center was ultimately not possible, the trial was streamlined to a single-center design. Consequently, enrollment at the Austrian center was refined so that at least 102 participants would reach the primary endpoint, thus meeting the original sample-size requirement. This administrative change was made prior to any analyses and does not affect the prespecified endpoints or procedures.

Interventions

• Device Transcranial pulse stimulation Verum
  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.
• Device Transcranial pulse stimulation Sham
  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.

Primary outcome measures

• Fatigue Impact Scale (FIS) [Time frame: Baseline - 1 week after stimulation - 1 month after stimulation]

Secondary outcome measures (12)

• Beck Depression Inventory (BDI-II) [Time frame: Baseline - 1 week after stimulation - 1 month after stimulation]
• Montreal Cognitive Assessment (MOCA) [Time frame: Baseline - 1 week after stimulation - 1 month after stimulation]
• 36-Item Short Form Health Survey (SF-36) [Time frame: Baseline - 1 week after stimulation - 1 month after stimulation]
• Trail Making Test A and B (TMT-A and TMT-B) [Time frame: Baseline - 1 week after stimulation - 1 month after stimulation]
• Positive and Negative Affect Schedule (PANAS) [Time frame: Baseline - 1 week after stimulation - 1 month after stimulation]
• Beck Anxiety Inventory (BAI) [Time frame: Baseline - 1 week after stimulation - 1 month after stimulation]
• Six Minute Walking Test (6MWT) [Time frame: Baseline - 1 week after stimulation - 1 month after stimulation]
• Test of Attentional Performance (TAP) [Time frame: Baseline - 1 week after stimulation - 1 month after stimulation]
• Verbal Learning and Memory Test (VLMT) [Time frame: Baseline - 1 week after stimulation - 1 month after stimulation]
• Stroop color word test (STROOP) [Time frame: Baseline - 1 week after stimulation - 1 month after stimulation]
• Satisfaction With Life Scale (SWLS) [Time frame: Baseline - 1 week after stimulation - 1 month after stimulation]
• Somatization subscale of the Symptom Check List-90-R (SCL-90-R SOM) [Time frame: Baseline - 1 week after stimulation - 1 month after stimulation]

Eligibility criteria

Inclusion criteria

• Signed written informed consent
• PCR-confirmed SARS-CoV-2 infection, laboratory confirmed antibody detection for SARS-CoV-2, or physician-verified COVID-19 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
• Relevant corticosteroid treatments administered within 6 weeks prior to the first application
• Tumor of the head if relevant for treatment
• Blood clotting disorders
• Participation in other studies

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Austria · 1 center

• Medical University of Vienna — Vienna

Publications

• Beisteiner R, Matt E, Fan C, Baldysiak H, Schonfeld M, Philippi Novak T, Amini A, Aslan T, Reinecke R, Lehrner J, Weber A, Reime U, Goldenstedt C, Marlinghaus E, Hallett M, Lohse-Busch H. Transcranial Pulse Stimulation with Ultrasound in Alzheimer's Disease-A New Navigated Focal Brain Therapy. Adv Sci (Weinh). 2019 Dec 23;7(3):1902583. doi: 10.1002/advs.201902583. eCollection 2020 Feb. PMID 32042569
• Beisteiner R, Hallett M, Lozano AM. Ultrasound Neuromodulation as a New Brain Therapy. Adv Sci (Weinh). 2023 May;10(14):e2205634. doi: 10.1002/advs.202205634. Epub 2023 Mar 24. PMID 36961104
• Cont C, Stute N, Galli A, Schulte C, Logmin K, Trenado C, Wojtecki L. Retrospective real-world pilot data on transcranial pulse stimulation in mild to severe Alzheimer's patients. Front Neurol. 2022 Sep 14;13:948204. doi: 10.3389/fneur.2022.948204. eCollection 2022. PMID 36188380
• Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, McCarthy P, Lange F, Andersson JLR, Griffanti L, Duff E, Jbabdi S, Taschler B, Keating P, Winkler AM, Collins R, Matthews PM, Allen N, Miller KL, Nichols TE, Smith SM. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature. 2022 Apr;604(7907):697-707. doi: 10.1038/s41586-022-04569-5. Epub 2022 Mar 7. PMID 35255491
• Ashraf N, Abou Shaar B, Taha RM, Arabi TZ, Sabbah BN, Alkodaymi MS, Omrani OA, Makhzoum T, Almahfoudh NE, Al-Hammad QA, Hejazi W, Obeidat Y, Osman N, Al-Kattan KM, Berbari EF, Tleyjeh IM. A systematic review of trials currently investigating therapeutic modalities for post-acute COVID-19 syndrome and registered on WHO International Clinical Trials Platform. Clin Microbiol Infect. 2023 May;29(5):57 PMID 36642173
• Han Q, Zheng B, Daines L, Sheikh A. Long-Term Sequelae of COVID-19: A Systematic Review and Meta-Analysis of One-Year Follow-Up Studies on Post-COVID Symptoms. Pathogens. 2022 Feb 19;11(2):269. doi: 10.3390/pathogens11020269. PMID 35215212
• Kubota T, Kuroda N, Sone D. Neuropsychiatric aspects of long COVID: A comprehensive review. Psychiatry Clin Neurosci. 2023 Feb;77(2):84-93. doi: 10.1111/pcn.13508. Epub 2022 Dec 12. PMID 36385449
• Linnhoff S, Koehler L, Haghikia A, Zaehle T. The therapeutic potential of non-invasive brain stimulation for the treatment of Long-COVID-related cognitive fatigue. Front Immunol. 2023 Jan 9;13:935614. doi: 10.3389/fimmu.2022.935614. eCollection 2022. PMID 36700201

Identifiers

NCT: NCT06178952 · 102307161 · 102307161

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗