Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0835 or +27 21 938 0967
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202403516079512 Date of Registration: 05/03/2024
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Treatment of Progressive Multiple Sclerosis-related Cognitive Impairment, Fatigue, and Depression Using Repetitive Transcranial Magnetic Stimulation
Official scientific title Treatment of Progressive Multiple Sclerosis-related Cognitive Impairment, Fatigue, and Depression Using Repetitive Transcranial Magnetic Stimulation
Brief summary describing the background and objectives of the trial Background: Multiple sclerosis (MS) is the most frequent central nervous system disease of early and mid-adulthood. Cognitive impairment, fatigue, and depression are prevalent in MS, however, these symptoms have been underestimated in the past. It is now recognized that these symptoms are linked to considerable disability and negatively affect patients’ quality of life. Sandyk, 1998 showed in various studies how electromagnetic stimulation manages to improve the visual and cognitive deficit associated with MS, as well as reducing the symptomatic exacerbation. Many studies were conducted on the application of conventional repetitive Transcranial Magnetic Stimulation (rTMS) to treat such disabling symptoms as cognitive impairment, depression, and fatigue. These studies potentially showed controversies due to heterogeneous MS symptomatology and heterogeneous research methodologies, which is a fundamental issue to be resolved in the future. Thus, further trials replicating the results will help establish the exact level of evidence for the use of rTMS as a supplementary treatment for MS. Objectives: The primary objective is to investigate the efficacy of high frequency rTMS on cognitive impairment, fatigue, and depression in a sample of Egyptian progressive MS patients. The secondary objective is to evaluate the effects of these protocols on the patients’ MS-related sphincteric dysfunction.
Type of trial RCT
Acronym (If the trial has an acronym then please provide)
Disease(s) or condition(s) being studied Nervous System Diseases
Sub-Disease(s) or condition(s) being studied
Purpose of the trial Treatment: Devices
Anticipated trial start date 01/04/2024
Actual trial start date 28/03/2024
Anticipated date of last follow up 01/04/2025
Actual Last follow-up date 24/06/2025
Anticipated target sample size (number of participants) 60
Actual target sample size (number of participants) 60
Recruitment status Completed
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Simple randomization using a randomization table created by a computer software program Allocation was determined by the holder of the sequence who is situated off site Masking/blinding used Outcome Assessors,Participants
Parallel: different groups receive different interventions at same time during study Randomised Simple randomization using a randomization table created by a computer software program Allocation was determined by the holder of the sequence who is situated off site Masking/blinding used
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Real repetitive Transcranial Magnetic Stimulation of DLPFC 6 sessions: Each session lasts for 580 seconds and consists of 1000 pulses with a frequency of 10 Hz, at 90% of resting motor threshold for DLPFC stimulation. 6 every-other-day sessions (over 2 weeks) Resting motor threshold is first determined in the abductor pollicis brevis according to the method described by Rossini et al., 1994. Each session lasts for 580 seconds and consists of 1000 pulses with a frequency of 10 Hz, at 90% of resting motor threshold for DLPFC stimulation, in 25 trains, 40 pulses per train with 20 seconds inter-train interval. The coil is held in the optimal scalp position with the handle pointing backwards at 45° of the sagittal plane to ensure that the induced electric field be perpendicular to the underlying gyrus. The site of stimulation of left DLPFC corresponds to F3 of 10-20 system of EEG. MagVenture MagPro X100 repetitive transcranial magnetic stimulator (Farum, Denmark) with Magoption and a 75-mm figure-of-eight coil (MagVenture cool B65) will be used. 20
Experimental Group Real repetitive Transcranial Magnetic Stimulation over SMA 6 sessions: Each session lasts for 580 seconds and consists of 1000 pulses with a frequency of 10 Hz, at 110% of resting motor threshold for SMA stimulation. 6 every-other-day sessions (over 2 weeks) Resting motor threshold is first determined in the abductor pollicis brevis according to the method described by Rossini et al., 1994. Each session lasts for 580 seconds and consists of 1000 pulses with a frequency of 10 Hz, at 110% of resting motor threshold for SMA stimulation, in 25 trains, 40 pulses per train with 20 seconds inter-train interval. The coil is held in the optimal scalp position to ensure that the induced electric field be perpendicular to the underlying gyrus. The site of stimulation for SMA corresponds to 2 cm anterior to Cz. MagVenture MagPro X100 repetitive transcranial magnetic stimulator (Farum, Denmark) with Magoption and a 75-mm figure-of-eight coil (MagVenture cool B65) will be used. 20
Control Group Sham repetitive Transcranial Magnetic Stimulation of DLPFC or of SMA Similar pattern of stimulation of the experimental groups which will receive intervention at DLPFC or at SMA but using an inactive coil that is shielded yet optically identical to the active coil. 6 every-other-day sessions (over 2 weeks) Similar pattern of stimulation of the experimental group which will receive intervention at DLPFC or at SMA but using an inactive coil that is shielded yet optically identical to the active coil. It produces sounds and sensations similar to the active coil but does not produce therapeutic effects. Later on, patients in this group will cross over to receive real rTMS over DLPFC or over SMA . In this control group, half of the patients will receive sham at at DLPFC, and the other half at SMA. After the last follow-up, each patient will receive real rTMS over the same scalp site where sham was applied to them. 20 Placebo
Experimental Group Real repetitive Transcranial Magnetic Stimulation over SMA 6 sessions: Each session lasts for 580 seconds and consists of 1000 pulses with a frequency of 10 Hz, at 110% of resting motor threshold for SMA stimulation. 6 every-other-day sessions (over 2 weeks) Resting motor threshold is first determined in the abductor pollicis brevis according to the method described by Rossini et al., 1994. Each session lasts for 580 seconds and consists of 1000 pulses with a frequency of 10 Hz, at 110% of resting motor threshold for SMA stimulation, in 25 trains, 40 pulses per train with 20 seconds inter-train interval. The coil is held in the optimal scalp position to ensure that the induced electric field be perpendicular to the underlying gyrus. The site of stimulation for SMA corresponds to 2 cm anterior to Cz. MagVenture MagPro X100 repetitive transcranial magnetic stimulator (Farum, Denmark) with Magoption and a 75-mm figure-of-eight coil (MagVenture cool B65) will be used. 20
Control Group Sham repetitive Transcranial Magnetic Stimulation of DLPFC or of SMA Similar pattern of stimulation of the experimental groups which will receive intervention at DLPFC or at SMA but using an inactive coil that is shielded yet optically identical to the active coil. 6 every-other-day sessions (over 2 weeks) Similar pattern of stimulation of the experimental group which will receive intervention at DLPFC or at SMA but using an inactive coil that is shielded yet optically identical to the active coil. It produces sounds and sensations similar to the active coil but does not produce therapeutic effects. Later on, patients in this group will cross over to receive real rTMS over DLPFC or over SMA . In this control group, half of the patients will receive sham at at DLPFC, and the other half at SMA. After the last follow-up, each patient will receive real rTMS over the same scalp site where sham was applied to them. 20 Placebo
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
-Definite MS patients according to 2017 revisions of the McDonald criteria. -Progressive types of MS: Patient must fulfill diagnostic criteria of either: Secondary progressive MS (SPMS) or Primary progressive MS (PPMS) -Free of clinical relapses for at least 3 months prior to inclusion. -Free of steroid treatment for at least 6 weeks prior to inclusion. -No change in their medications, whether disease modifying treatment or symptomatic therapy for at least 3 months if applicable. -EDSS score ≤ 6 points and stable over the past 3 months. -A score of <34 on Symbol Digit Modalities Test, a score of ≥ 12 on the Beck Depression Inventory (Beck et al., 1961), a score of ≥ 38 on the Modified Fatigue Impact Scale. -Level of education: at least can read and write. -Written informed consent from the participants -Conditions that could affect the participants’ level of cognition, fatigue, or depression, including; pregnancy, history of substance use disorder, history of significant neurological disorder other than MS, psychiatric, endocrinological, hepatic, renal, collagen, or other systemic comorbidities that could affect these symptoms. -Contraindication to TMS: history of seizures, skull bone defects, metal fragments in the head, implanted metallic devices such as cardiac pacemakers, cochlear implants, medical pumps…, etc. -Illiterate patients. Adult: 18 Year(s)-44 Year(s),Middle Aged: 45 Year(s)-64 Year(s) 18 Year(s) 65 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 12/02/2024 The Research Ethics Committee at the Faculty of Medicine Ain Shams University
Ethics Committee Address
Street address City Postal code Country
38 Abbassia Square Cairo 11591 Egypt
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome To investigate the efficacy of high frequency rTMS on cognitive impairment using Symbol Digit Modalities Test, fatigue using Arabic version of Modified Fatigue Impact Scale, and depression using Arabic version of Beck Depression inventory in a sample of Egyptian progressive MS patients. Immediately after the last stimulation session, 4 weeks and at 12 weeks after the end of the intervention.
Secondary Outcome To evaluate the effects of high frequency rTMS on the patients’ MS-related sphincteric dysfunction using the Arabic International Consultation on Incontinence Questionnaire-Short Form Scale, and on the patients’ walking performance using Timed 25-Foot walk test and Functional Ambulation Category. Immediately after the last stimulation session, at 4 weeks and at 12 weeks after the end of the intervention.
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Multiple Sclerosis unit Neurology Department Ain Shams University 38 Abbassia Square Cairo 11591 Egypt
FUNDING SOURCES
Name of source Street address City Postal code Country
Science Technology and Innovation Funding Authority 101 Kasr Al-Ainy Cairo Egypt
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Science Technology and Innovation Funding Authority 101 Kasr Al-Ainy Cairo 11694 Egypt Funding Agency
Secondary Sponsor Neurology department Ain Shams University 38 Abbassia Square Cairo 11591 Egypt University
COLLABORATORS
Name Street address City Postal code Country
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Nevine El Nahas nevine_elnahas@med.asu.edu.eg +201227910517 38 Abbassia square
City Postal code Country Position/Affiliation
Cairo 11591 Egypt Professor of Neurology Ain Shams University
Role Name Email Phone Street address
Public Enquiries Azza Abdelnasser azza.abdelnasser@med.asu.edu.eg +201001240246 38 Abbassia square
City Postal code Country Position/Affiliation
Cairo 11591 Egypt Professor of Neurology Ain Shams University
Role Name Email Phone Street address
Scientific Enquiries Maha Sabry sabrymaha1@med.asu.edu.eg +201092998698 38 Abbassia square
City Postal code Country Position/Affiliation
Cairo 11591 Egypt Assistant Lecturer of Neurology Ain Shams University
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes All of the individual participant data collected during the trial, after deidentification. Analytic Code,Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol Immediately following publication, ending 6 months following article publication. Open access, For individual participant metanalysis, Data will be made available on scientifically-sound basis, Data requesting should be directed to the principal investigator via E-mail
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Actual trial start date 04/05/2024 Update 28 Mar 2024
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Completion date 24/06/2025 Update 24 Jun 2025
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Final no of participants 22/01/2025 Update 60
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Recruitment status 25/05/2024 Update Not yet recruiting Recruiting
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Recruitment status 22/01/2025 Update Recruiting Closed to recruitment,follow-up continuing
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Recruitment status 24/06/2025 Update Closed to recruitment,follow-up continuing Completed
Section Name Field Name Date Reason Old Value Updated Value
Study Design Intervention assignment 22/01/2025 Update Crossover: all participants receive all interventions in different sequence during study Parallel: different groups receive different interventions at same time during study
Section Name Field Name Date Reason Old Value Updated Value
Eligibility Inclusion criteria 04/05/2024 Typing error -Definite MS patients according to 2017 revisions of the McDonald criteria. -Progressive types of MS: Patient must fulfill diagnostic criteria of either: Secondary progressive MS (SPMS) or Primary progressive MS (PPMS) -Free of clinical relapses for at least 3 months prior to inclusion. -Free of steroid treatment for at least 6 weeks prior to inclusion. -No change in their medications, whether disease modifying treatment or symptomatic therapy for at least 3 months if applicable. -EDSS score below 6 points and stable over the past 3 months. -A score of <34 on Symbol Digit Modalities Test, a score of ≥ 12 on the Beck Depression Inventory (Beck et al., 1961), a score of ≥ 38 on the Modified Fatigue Impact Scale. -Level of education: at least can read and write. -Written informed consent from the participants -Definite MS patients according to 2017 revisions of the McDonald criteria. -Progressive types of MS: Patient must fulfill diagnostic criteria of either: Secondary progressive MS (SPMS) or Primary progressive MS (PPMS) -Free of clinical relapses for at least 3 months prior to inclusion. -Free of steroid treatment for at least 6 weeks prior to inclusion. -No change in their medications, whether disease modifying treatment or symptomatic therapy for at least 3 months if applicable. -EDSS score ≤ 6 points and stable over the past 3 months. -A score of <34 on Symbol Digit Modalities Test, a score of ≥ 12 on the Beck Depression Inventory (Beck et al., 1961), a score of ≥ 38 on the Modified Fatigue Impact Scale. -Level of education: at least can read and write. -Written informed consent from the participants
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 06/07/2026 2-4 cm anterior to Cz is named SMA; while pre SMA is the anatomic name given if 6 cm anterior to Cz.. this was just misnaming Experimental Group, Real repetitive Transcranial Magnetic Stimulation over SMA, 6 sessions: Each session lasts for 580 seconds and consists of 1000 pulses with a frequency of 10 Hz, at 110% of resting motor threshold for SMA stimulation., 6 every-other-day sessions (over 2 weeks), Resting motor threshold is first determined in the abductor pollicis brevis according to the method described by Rossini et al., 1994. Each session lasts for 580 seconds and consists of 1000 pulses with a frequency of 10 Hz, at 110% of resting motor threshold for pre SMA stimulation, in 25 trains, 40 pulses per train with 20 seconds inter-train interval. The coil is held in the optimal scalp position to ensure that the induced electric field be perpendicular to the underlying gyrus. The site of stimulation for SMA corresponds to 2 cm anterior to Cz. MagVenture MagPro X100 repetitive transcranial magnetic stimulator (Farum, Denmark) with Magoption and a 75-mm figure-of-eight coil (MagVenture cool B65) will be used. , 20,
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 06/07/2026 2-4 cm anterior to Cz is named SMA; while pre SMA is the anatomic name given if 6 cm anterior to Cz.. this was just misnaming Experimental Group, Real repetitive Transcranial Magnetic Stimulation over SMA, 6 sessions: Each session lasts for 580 seconds and consists of 1000 pulses with a frequency of 10 Hz, at 110% of resting motor threshold for SMA stimulation., 6 every-other-day sessions (over 2 weeks), Resting motor threshold is first determined in the abductor pollicis brevis according to the method described by Rossini et al., 1994. Each session lasts for 580 seconds and consists of 1000 pulses with a frequency of 10 Hz, at 110% of resting motor threshold for pre SMA stimulation, in 25 trains, 40 pulses per train with 20 seconds inter-train interval. The coil is held in the optimal scalp position to ensure that the induced electric field be perpendicular to the underlying gyrus. The site of stimulation for SMA corresponds to 2 cm anterior to Cz. MagVenture MagPro X100 repetitive transcranial magnetic stimulator (Farum, Denmark) with Magoption and a 75-mm figure-of-eight coil (MagVenture cool B65) will be used. , 20, Experimental Group, Real repetitive Transcranial Magnetic Stimulation over SMA, 6 sessions: Each session lasts for 580 seconds and consists of 1000 pulses with a frequency of 10 Hz, at 110% of resting motor threshold for SMA stimulation., 6 every-other-day sessions (over 2 weeks), Resting motor threshold is first determined in the abductor pollicis brevis according to the method described by Rossini et al., 1994. Each session lasts for 580 seconds and consists of 1000 pulses with a frequency of 10 Hz, at 110% of resting motor threshold for SMA stimulation, in 25 trains, 40 pulses per train with 20 seconds inter-train interval. The coil is held in the optimal scalp position to ensure that the induced electric field be perpendicular to the underlying gyrus. The site of stimulation for SMA corresponds to 2 cm anterior to Cz. MagVenture MagPro X100 repetitive transcranial magnetic stimulator (Farum, Denmark) with Magoption and a 75-mm figure-of-eight coil (MagVenture cool B65) will be used. , 20,
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 22/01/2025 Re-formatting/ Re-formulating/ Re-description of the placebo group written on initial registration at PACTR. Better to consider/ combine it as one placebo group rather than subclassifying as two placebo groups; as the intervention is the same and the site of brain stimulation will not change the non therapeutic nature of the sham coil. To reduce patient bias, beyond blinding, sham and real stimulation is applied over the same scalp area. That is the point. The update done is a better way to introduce/ describe/ express the study intention. Control Group, Sham repetitive Transcranial Magnetic Stimulation of DLPFC, Similar pattern of stimulation of the experimental group which will receive intervention at DLPFC but using an inactive coil that is shielded yet optically identical to the active coil., 6 every-other-day sessions (over 2 weeks), Similar pattern of stimulation of the experimental group which will receive intervention at DLPFC but using an inactive coil that is shielded yet optically identical to the active coil. It produces sounds and sensations similar to the active coil but does not produce therapeutic effects. Later on, patients in this group will cross over to receive real rTMS over as proposed., 10, Placebo Control Group, Sham repetitive Transcranial Magnetic Stimulation of DLPFC or of pre SMA, Similar pattern of stimulation of the experimental groups which will receive intervention at DLPFC or at pre SMA but using an inactive coil that is shielded yet optically identical to the active coil., 6 every-other-day sessions (over 2 weeks), Similar pattern of stimulation of the experimental group which will receive intervention at DLPFC or at pre SMA but using an inactive coil that is shielded yet optically identical to the active coil. It produces sounds and sensations similar to the active coil but does not produce therapeutic effects. Later on, patients in this group will cross over to receive real rTMS over DLPFC or over pre SMA . In this control group, half of the patients will receive sham at at DLPFC, and the other half at pre SMA. After the last follow-up, each patient will receive real rTMS over the same scalp site where sham was applied to them., 20, Placebo
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 06/07/2026 Re-formatting/ Re-formulating/ Re-description of the placebo group written on initial registration at PACTR. Better to consider/ combine it as one placebo group rather than subclassifying as two placebo groups; as the intervention is the same and the site of brain stimulation will not change the non therapeutic nature of the sham coil. To reduce patient bias, beyond blinding, sham and real stimulation is applied over the same scalp area. That is the point. The update done is a better way to introduce/ describe/ express the study intention. Mirroring active SMA group, 2-4 cm anterior to Cz is named SMA; while pre SMA is the anatomic name given if 6 cm anterior to Cz.. this was just misnaming Control Group, Sham repetitive Transcranial Magnetic Stimulation of DLPFC or of pre SMA, Similar pattern of stimulation of the experimental groups which will receive intervention at DLPFC or at pre SMA but using an inactive coil that is shielded yet optically identical to the active coil., 6 every-other-day sessions (over 2 weeks), Similar pattern of stimulation of the experimental group which will receive intervention at DLPFC or at pre SMA but using an inactive coil that is shielded yet optically identical to the active coil. It produces sounds and sensations similar to the active coil but does not produce therapeutic effects. Later on, patients in this group will cross over to receive real rTMS over DLPFC or over pre SMA . In this control group, half of the patients will receive sham at at DLPFC, and the other half at pre SMA. After the last follow-up, each patient will receive real rTMS over the same scalp site where sham was applied to them., 20, Placebo Control Group, Sham repetitive Transcranial Magnetic Stimulation of DLPFC or of SMA, Similar pattern of stimulation of the experimental groups which will receive intervention at DLPFC or at SMA but using an inactive coil that is shielded yet optically identical to the active coil., 6 every-other-day sessions (over 2 weeks), Similar pattern of stimulation of the experimental group which will receive intervention at DLPFC or at SMA but using an inactive coil that is shielded yet optically identical to the active coil. It produces sounds and sensations similar to the active coil but does not produce therapeutic effects. Later on, patients in this group will cross over to receive real rTMS over DLPFC or over SMA . In this control group, half of the patients will receive sham at at DLPFC, and the other half at SMA. After the last follow-up, each patient will receive real rTMS over the same scalp site where sham was applied to them., 20, Placebo
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 22/01/2025 Re-formatting/ Re-formulating/ Re-description of the placebo group written on initial registration at PACTR. Better to consider/ combine it as one placebo group rather than subclassifying as two placebo groups; as the intervention is the same and the site of brain stimulation will not change the non therapeutic nature of the sham coil. To reduce patient bias, beyond blinding, sham and real stimulation is applied over the same scalp area. That is the point. The update done is a better way to introduce/ describe/ express the study intention. Control Group, Sham repetitive Transcranial Magnetic Stimulation of pre SMA, Similar pattern of stimulation of the experimental group which will receive intervention at pre-SMA but using an inactive coil that is shielded yet optically identical to the active coil. , 6 every-other-day sessions (over 2 weeks), Similar pattern of stimulation of the experimental group which will receive intervention at pre-SMA but using an inactive coil that is shielded yet optically identical to the active coil. It produces sounds and sensations similar to the active coil but does not produce therapeutic effects. Later on, patients in this group will cross over to receive real rTMS over as proposed., 10, Placebo
Section Name Field Name Date Reason Old Value Updated Value
Outcome OutCome List 25/03/2024 Adding another item in the secondary aim. Secondary Outcome, To evaluate the effects of high frequency rTMS on the patients’ MS-related sphincteric dysfunction using the Arabic International Consultation on Incontinence Questionnaire-Short Form Scale ., Immediately after the last stimulation session, at 4 weeks and at 12 weeks after the end of the intervention. Secondary Outcome, To evaluate the effects of high frequency rTMS on the patients’ MS-related sphincteric dysfunction using the Arabic International Consultation on Incontinence Questionnaire-Short Form Scale, and on the patients’ walking performance using Timed 25-Foot walk test and Functional Ambulation Category., Immediately after the last stimulation session, at 4 weeks and at 12 weeks after the end of the intervention.