The objective of the present study is to demonstrate treatment efficacy of transcranialpulse 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 comparedto a sham (placebo) condition.
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 [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, SF-36 and BI-PEM) 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:
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. 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.
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.
Inclusion Criteria:
- Signed written informed consent
- PCR-confirmed SARS-CoV-2 infection or laboratory confirmed antibody detection for
SARS-CoV-2
- 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
- Tumor of the head if relevant for treatment
- Blood clotting disorders
- Participation in other studies
Medical University of Vienna
Vienna, Austria
Università Campus Bio-Medico di Roma
Rome, Italy
Roland Beisteiner, Prof.
+43/(0)1 40400-34080
roland.beisteiner@meduniwien.ac.at
Michael Mitterwallner, Dr.
+43 650 9626003
michael.mitterwallner@meduniwien.ac.at
Roland Beisteiner, Prof., Principal Investigator
Medical University of Vienna