rTMS Add on Value for Amelioration of Negative Symptoms of Schizophrenia (RADOVAN)

Treatment of depression with repetitive transcranial magnetic stimulation (rTMS) has shown high evidence using high-frequency left dorsolateral prefrontal cortex (DLPFC) stimulation. The treatment of negative symptoms with the same protocol in schizophrenia is considered as possible effective. Theta burst stimulation is a new protocol which is characterized by shorter sessions showing first evidence that it's efficacy is comparable to the high-frequency rTMS. In this randomized placebo-controlled study the efficacy of high-frequency rTMS and TBS are evaluated.

Study Overview

• Status: Recruiting
• Conditions: Schizophrenia; Negative Symptoms With Primary Psychotic Disorder
• Intervention / Treatment: Device: high-frequency rTMS; Device: TBS; Device: placebo

Detailed Description

In this randomized placebo-controlled study the efficacy of high-frequency rTMS and TBS are evaluated. The active study arms are high-frequency rTMS and iTBS of the left dorsolateral prefrontal cortex to treat negative symptoms in schizophrenia. The control arm will include the same number of patients as each active arm and includes both sham rTMS and sham iTBS in the same proportion as the active treatments.

Standards of the trial will be harmonized across four clinical centers with the aim to pool data for analysis. Each center is responsible for ethical approval and adherence to good clinical practice by itself (Sponsor).

Interim analysis: Several meta-analyses of the effect of rTMS/iTBS on negative symptoms in schizophrenia showing heterogeneous effect sizes have been published since begin of the trial. Thefore, we added an interim analysis after inclusion of at least 15 patients in each arm to the protocol. In case of null findings and low effect sizes (no differences of either rTMS or TBS vs. sham in the primary outcome), we would terminate the trial.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Tobias Hebel, MD; Phone Number: +49-941-941-1250; Email: tobias.hebel@medbo.de
• Study Contact Backup: Name: Martin Schecklmann, PhD; Phone Number: +49-941-941-1250; Email: martin.schecklmann@medbo.de

Study Locations

• Czechia
  • Brno, Czechia
    • Recruiting
    • Brno University Hospital
    • Contact: Libor Ustohal
  • Ostrava, Czechia
    • Recruiting
    • University Hospital Ostrava
    • Contact: Tomas Skront
• Germany
  • Aachen, Germany
    • Not yet recruiting
    • University Hospital Aachen
    • Contact: Timm Pöppl
  • Regensburg, Germany
    • Recruiting
    • University of Regensburg
    • Contact: Tobias Hebel, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ICD-10: schizophrenia with primarily negative symptoms
• Age: 18-75 years
• at least 35 Points at the composite score of the SANS
• stabe medication during the last 2 weeks (at the investigator's discretion)
• written informed consent (by the patient or guardian)

Exclusion Criteria:

• clinically relevant unstable concomitant somatic diseases
• previous treatment by rTMS
• conditions in which TMS may not be applicated, as e.g., cardiac pacemakers or ferromagnetic implants
• history of epileptic seizures
• current substance or alcohol abuse, or clinically relevant comorbidity (according to M.I.N.I. interview)
• unacceptable concomitant medication (benzodiazepines in higher doses, e.g., Lorazepam > 2 mg/d, Diazepam > 10 mg/d)
• insufficient knowledge of the language of the country of the treatment site
• pregnancy and nursing period
• current statutory hospitalisation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: high-frequency repetitive transcranial magnetic stimulation; repetitive transcranial magnetic stimulation over left dorsolateral prefrontal cortex using 3000 pulses applied with 10Hz and 120% resting motor threshold	Device: high-frequency rTMS; repetitive transcranial magnetic stimulation
Experimental: theta burst stimulation; intermittent theta burst stimulation over left dorsolateral prefrontal cortex using 600 pulses applied in trains of 10 triplets/bursts (50Hz) with 8s intertrain-interval and 120% resting motor threshold	Device: TBS; theta burst stimulation
Placebo Comparator: sham rTMS; half of the patients with high-frequency repetitive transcranial magnetic stimulation and half of the patients with theta burst Stimulation with angled coil (45 degree) or sham coil	Device: placebo; placebo transcranial magnetic stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Scale for the Assessement of Negative Symptoms (SANS)	negative symptoms in schizophrenia with 25 items and a range 0-125 with higher score representing more symptoms	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Depression Inventory (MDI)	measurment of depressivity: 10 items with a range 0-50 and higher values indicating higher scores	2 weeks, 4 weeks, 12 weeks
Clinical global impression (CGI)	measure of overall symptom severity and treatment response on a scale 1-7 with higher scores presenting more symptoms	2 weeks, 4 weeks, 12 weeks
Hamilton depression rating scale (HDRS)	measurment of depressivity: 21 items with a range 0-65 and higher values indicating higher scores	2 weeks, 4 weeks, 12 weeks
Scale for the Assessement of Negative Symptoms (SANS)	negative symptoms in schizophrenia with 25 items and a range 0-125 with higher score representing more symptoms	2 weeks, 4 weeks, 12 weeks
Positive and Negative syndrome scale (PANSS)	positive and negative symptoms in schizophrenia with 30 items and a range 30-210 with higher scores representing more symptoms (total score, score for positive, negative symptoms and for general psychopathology)	2 weeks, 4 weeks, 12 weeks
Calgary Depression Scale for Schizophrenia (CDSS)	Calgary Depression Scale for Schizophrenia	2 weeks, 4 weeks, 12 weeks
Memory span test (digit span)	test for short-term and working memory	4 weeks, 12 weeks
test of attention (d2)	test of attention for measurement of concentration	4 weeks, 12 weeks
Resting state electroencephalogram (EEG)	measurement of resting state electrophysiologic activity as indicated by frequency analysis and rTMS-evoked activity	4 weeks
magnetic resonance imaging (MRI)	structural, anatomical, diffusion weighted magnetic resonance imaging	4 weeks
cigarettes	number of smoked cigarettes per week	4 weeks, 12 weeks

Collaborators and Investigators

• Sponsor: University of Regensburg
• Collaborators: University Hospital Ostrava; Brno University Hospital; University Hospital, Aachen
• Investigators: Study Chair: Berthold Langguth, MD, PhD, University of Regensburg

Publications and helpful links

General Publications

• Hebel T, Langguth B, Schecklmann M, Schoisswohl S, Staudinger S, Schiller A, Ustohal L, Sverak T, Horky M, Kasparek T, Skront T, Hyza M, Poeppl TB, Riester ML, Schwemmer L, Zimmermann S, Sakreida K. Rationale and study design of a trial to assess rTMS add-on value for the amelioration of negative symptoms of schizophrenia (RADOVAN). Contemp Clin Trials Commun. 2022 Jan 20;26:100891. doi: 10.1016/j.conctc.2022.100891. eCollection 2022 Apr.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2020
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): April 30, 2024

Study Registration Dates

• First Submitted: March 16, 2020
• First Submitted That Met QC Criteria: March 20, 2020
• First Posted (Actual): March 24, 2020

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 24, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders
• Other Study ID Numbers: 19-1616-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No