Effects of Dimethyl Fumarate on Cognitive Performance and Brain Abnormalities in Multiple Sclerosis.

NCT05811949 | Completed

• 1 other identifier: MSDMF_2020
• Study Type: observational
• Target: 52
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this observational study is to evaluate the slowing/reduction of cognitive dysfunction progression and to evaluate grey matter (GM) and thalamus structural changes in Relapsing-Remitting Multiple Sclerosis (RRMS) patients after 12 months of treatment with Dimethyl Fumarate (DMF). The main questions it aims to answer are:

• Can DMF slow or reduce the progression of cognitive dysfunction in RRMS patients?
• Can DMF slow the reduction of brain volume in RRMS patients? At baseline visit, RRMS patients undergo extensive neurological examination in which their disability is evaluated by using Expanded Disability Status Scale (EDSS). The efficacy assessments of this study are:
• The Brief Repeatable Neuropsychological Battery (BRB);
• Executive functions: Delis-Kaplan Function System (DKEFS) scale - Sorting Test.

Conditions

Multiple Sclerosis

Outcome Measures

Primary Outcomes (28)

• Change in subjects' cognitive performance

  Change from baseline in Selective Reminding Test - Long-Term Storage (SRT-LTS) Raw Score of Brief Repeatable Battery (BRB) at 6 months. This is one of the five tests of BRB for episodic memory (verbal learning and delayed recall). A word recalled on two consecutive trials is considered to have entered long-term storage (LTS) on the first of these trials and scored as LTS on all following trials. The total score ranged from 0 to 72. Higher values represent a better outcome.

  Month 0 Baseline to Month 6 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Selective Reminding Test - Consistent Long Term Retrieval (SRT-CLTR) Raw Score of Brief Repeatable Battery (BRB) at 6 months. This is one of the five tests of BRB for episodic memory (verbal learning and delayed recall). A word recalled on two consecutive trials is considered to have entered long-term storage (LTS) on the first of these trials and scored as LTS on all following trials. The total of the words in LTS of all six trials is then summed. If a word in LTS is consistently recalled on all subsequent trials, it is then scored as Consistent Long Term Retrieval (CLTR). The total of the words in CLTR of all six trials is summed. The total score ranged from 0 to 72. Higher values represent a better outcome.

  Month 0 Baseline to Month 6 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Spatial Recall Test (SPART) Raw Score of Brief Repeatable Battery (BRB) at 6 months. The spatial recall test assesses visuospatial learning and delayed recall. The total score ranged from 0 to 30. Higher values represent a better outcome.

  Month 0 Baseline to Month 6 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Symbol Digit Modalities Test (SDMT) Raw Score of Brief Repeatable Battery (BRB) at 6 months. Symbol Digit Modality Test (SDMT) for sustained attention and information processing speed. The score is the number of correct answers in 90 seconds. The total score ranged from 0 to 110. Higher values represent a better outcome.

  Month 0 Baseline to Month 6 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Paced Auditory Serial Addition Test - 3 Seconds (PASAT 3) Raw Score of Brief Repeatable Battery (BRB) at 6 months. Paced Auditory Serial Addition Test (PASAT) for working memory (and sustained attention and information processing speed). The total score ranged from 0 to 60. Higher values represent a better outcome.

  Month 0 Baseline to Month 6 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Paced Auditory Serial Addition Test - 2 (PASAT 2) Raw Score of Brief Repeatable Battery (BRB) at 6 months. Paced Auditory Serial Addition Test (PASAT) for working memory (and sustained attention and information processing speed). The total score ranged from 0 to 60. Higher values represent a better outcome.

  Month 0 Baseline to Month 6 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Selective Reminding Test - Delayed Recall (SRT-D) Raw Score of Brief Repeatable Battery (BRB) at 6 months. The tests SRT (Selective Reminding Test) for episodic memory (verbal learning and delayed recall).The total score ranged from 0 to 12. Higher values represent a better outcome.

  Month 0 Baseline to Month 6 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Spatial Recall Test - Delayed Recall (SPART-D) of Brief Repeatable Battery (BRB) at 6 months. Spatial Recall Test (SPART) for visuospatial learning and delayed recall. Spatial Recall Test (10/36): The spatial recall test assesses visuospatial learning and delayed recall (10/36-D). The total score ranged from 0 to 10. Higher values represent a better outcome.

  Month 0 Baseline to Month 6 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Word List Generation (WLG) of Brief Repeatable Battery (BRB) at 6 months. Word List Generation (COWAT/WLG): The COWAT assesses verbal fluency on semantic stimulus by asking the patient to produce as many words as possible belonging to a semantic category. No maximum range is available. Higher values represent a better outcome. The score is the number of correct words. The more words the patient pronounces, the better it is. We can imagine that the minimum value might be zero words, but it is not a score scale.

  Month 0 Baseline to Month 6 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Selective Reminding Test - Long-Term Storage (SRT-LTS) Raw Score of Brief Repeatable Battery (BRB) at 12 months. One of the five tests of BRB is SRT (Selective Reminding Test) for episodic memory (verbal learning and delayed recall). A word recalled on two consecutive trials is considered to have entered long-term storage (LTS) on the first of these trials and scored as LTS on all following trials. The total score ranged from 0 to 72. Higher values represent a better outcome.

  Month 0 Baseline to Month 12 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Selective Reminding Test - Consistent Long Term Retrieval (SRT-CLTR) Raw Score of Brief Repeatable Battery (BRB) at 12 months. One of the five tests of BRB is SRT (Selective Reminding Test) for episodic memory (verbal learning and delayed recall). A word recalled on two consecutive trials is considered to have entered long-term storage (LTS) on the first of these trials and scored as LTS on all following trials. The total of the words in LTS of all six trials is then summed. If a word in LTS is consistently recalled on all subsequent trials, it is then scored as Consistent Long Term Retrieval (CLTR). The total of the words in CLTR of all six trials is summed. The total score ranged from 0 to 72. Higher values represent a better outcome.

  Month 0 Baseline to Month 12 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Spatial Recall Test (SPART) Raw Score of Brief Repeatable Battery (BRB) at 12 months. The spatial recall test assesses visuospatial learning and delayed recall. The total score ranged from 0 to 30. Higher values represent a better outcome.

  Month 0 Baseline to Month 12 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Symbol Digit Modalities Test (SDMT) Raw Score of Brief Repeatable Battery (BRB) at 12 months. Symbol Digit Modality Test (SDMT) for sustained attention and information processing speed. The score is the number of correct answers in 90 seconds. The total score ranged from 0 to 110. Higher values represent a better outcome

  Month 0 Baseline to Month 12 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Paced Auditory Serial Addition Test - 3 Seconds (PASAT 3) Raw Score of Brief Repeatable Battery (BRB) at 12 months. Paced Auditory Serial Addition Test (PASAT) for working memory (and sustained attention and information processing speed). The total score ranged from 0 to 60. Higher values represent a better outcome.

  Month 0 Baseline to Month 12 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Paced Auditory Serial Addition Test - 2 (PASAT 2) Raw Score of Brief Repeatable Battery (BRB) at 12 months. +Paced Auditory Serial Addition Test (PASAT) for working memory (and sustained attention and information processing speed). The total score ranged from 0 to 60. Higher values represent a better outcome.

  Month 0 Baseline to Month 12 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Selective Reminding Test - Delayed Recall (SRT-D) Raw Score of Brief Repeatable Battery (BRB) at 12 months. The tests SRT (Selective Reminding Test) for episodic memory (verbal learning and delayed recall).The total score ranged from 0 to 12. Higher values represent a better outcome.

  Month 0 Baseline to Month 12 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Spatial Recall Test - Delayed Recall (SPART-D) of Brief Repeatable Battery (BRB) at 12 months. Spatial Recall Test (SPART) for visuospatial learning and delayed recall.Spatial Recall Test (10/36): The spatial recall test assesses visuospatial learning and delayed recall (10/36-D). The total score ranged from 0 to 10. Higher values represent a better outcome.

  Month 0 Baseline to Month 12 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Word List Generation (WLG) of Brief Repeatable Battery (BRB) at 12 months. Word List Generation (COWAT/WLG): The COWAT assesses verbal fluency on semantic stimulus by asking the patient to produce as many words as possible belonging to a semantic category. No maximum range is available. Higher values represent a better outcome. The score is the number of correct words. The more words the patient pronounces, the better it is. We can imagine that the minimum value might be zero words, but it is not a score scale.

  Month 0 Baseline to Month 12 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Delis-Kaplan Executive Function System (DKEFS) Condition 1: Free Sorting, Confirmed Correct Sort - Card Set 1+2 at 6 months. The standard form consists of the practice card set, card set 1 and card set 2. The alternate form consists of the same practice card set, card set 3 and card set 4. The DKFES test consisted of two testing procedures: free sorting and sort recognition. In free sorting, six scores are obtained: Confirmed Correct sorts for card sets 1 and 2 (or 3 and 4 for version B), sum of confirmed Correct Sorts. In sort recognition, a description score for card set 1 and 2 (or 3 and 4 for version B) is obtained, as well as the sum of description scores of both sets. The total score ranges from 0 to 16. Higher values represent a better outcome.

  Month 0 Baseline to Month 6 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in DKEFS Condition 1: Free Sorting, Free Sorting, Description Score, Card Set 1+2 at 6 months. The standard form consists of the practice card set, card set 1 and card set 2. The alternate form consists of the same practice card set, card set 3 and card set 4. In free sorting, six scores were obtained: Confirmed Correct sorts for card sets 1 and 2 (or 3 and 4 for version B), sum of confirmed Correct Sorts, Free Sorting Description score for card set 1 and 2 (or 3 and 4 for version B) and sum of Free Sorting Description scores. In sort recognition, a description score for card set 1 and 2 (or 3 and 4 for version B) was obtained, as well as the sum of description scores of both sets. The total score ranged from 0 to 64. Higher values represent a better outcome.

  Month 0 Baseline to Month 6 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in DKEFS Condition 2: Sort Recognition, Sort Recognition Description Score- Card Set 1+22 at 6 months. The standard form consists of the practice card set, card set 1 and card set 2. The alternate form consists of the same practice card set, card set 3 and card set 4. Free sorting and sort recognition. In free sorting, six scores were obtained: Confirmed Correct sorts for card sets 1 and 2 (or 3 and 4 for version B), sum of confirmed Correct Sorts, Free Sorting Description score for card set 1 and 2 (or 3 and 4 for version B) and sum of Free Sorting Description scores. The total score ranged from 0 to 64. Higher values represent a better outcome.

  Month 0 Baseline to Month 6 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in Delis-Kaplan Executive Function System (DKEFS) Condition 1: Free Sorting, Confirmed Correct Sort - Card Set 1+2 at 12 months. The standard form consists of the practice card set, card set 1 and card set 2. The alternate form consists of the same practice card set, card set 3 and card set 4. The DKFES test consisted of two testing procedures: free sorting and sort recognition. In free sorting, six scores are obtained: Confirmed Correct sorts for card sets 1 and 2 (or 3 and 4 for version B), sum of confirmed Correct Sorts. In sort recognition, a description score for card set 1 and 2 (or 3 and 4 for version B) is obtained, as well as the sum of description scores of both sets. The total score ranges from 0 to 16. Higher values represent a better outcome.

  Month 0 Baseline to Month 12 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in DKEFS Condition 1: Free Sorting, Free Sorting, Description Score, Card Set 1+2 at 12 months. The standard form consists of the practice card set, card set 1 and card set 2. The alternate form consists of the same practice card set, card set 3 and card set 4. In free sorting, six scores were obtained: Confirmed Correct sorts for card sets 1 and 2 (or 3 and 4 for version B), sum of confirmed Correct Sorts, Free Sorting Description score for card set 1 and 2 (or 3 and 4 for version B) and sum of Free Sorting Description scores. In sort recognition, a description score for card set 1 and 2 (or 3 and 4 for version B) was obtained, as well as the sum of description scores of both sets. The total score ranged from 0 to 64. Higher values represent a better outcome.

  Month 0 Baseline to Month 12 Follow-up

• Change in subjects' cognitive performance

  Change from baseline in DKEFS Condition 2: Sort Recognition, Sort Recognition Description Score - Card Set 1+22 at 12 months. The standard form consists of the practice card set, card set 1 and card set 2. The alternate form consists of the same practice card set, card set 3 and card set 4. Free sorting and sort recognition. In free sorting, six scores were obtained: Confirmed Correct sorts for card sets 1 and 2 (or 3 and 4 for version B), sum of confirmed Correct Sorts, Free Sorting Description score for card set 1 and 2 (or 3 and 4 for version B) and sum of Free Sorting Description scores. The total score ranged from 0 to 64. Higher values represent a better outcome.

  Month 0 Baseline to Month 12 Follow-up

• Changes brain MRI parameters

  Change from baseline GM and thalamus volume at 6 months.

  Month 0 Baseline to Month 6 Follow-up

• Changes brain MRI parameters

  Change from baseline GM and thalamus volume at 12 months.

  Month 0 Baseline to Month 12 Follow-up

• Changes brain MRI parameters

  Change from baseline DTI measures in the GM and thalamus at 6 months.

  Month 0 Baseline to Month 6 Follow-up

• Changes brain MRI parameters

  Change from baseline DTI measures in the GM and thalamus at 12 months.

  Month 0 Baseline to Month 12 Follow-up

Secondary Outcomes (1)

• Correlation between scores of cognitive battery and brain MRI parameters

  Baseline and 6 and 12 months after.

Other Outcomes (1)

• Difference between the two cohorts

  Baseline and 6 and 12 months after.

Study Arms (2)

RRMS patients with de novo DMF treatment

RRMS patients with de novo treatment who start DMF.

Drug: Dimethyl Fumarate 240 MG [Tecfidera]

RRMS patients switching to DMF.

RRMS patients who switch from first-line DMT treatment (interferon, glatiramer acetate, teriflunomide) to treatment with DMF.

Drug: Dimethyl Fumarate 240 MG [Tecfidera]

Interventions

Dimethyl Fumarate 240 MG [Tecfidera] DRUG

DMF is admnistered to RRMS patients who are candidates for treatment according to clinical practice at a dosage of 120 mg twice daily, increased to 240 mg twice daily after 7 days.

RRMS patients switching to DMF.; RRMS patients with de novo DMF treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

The study is conducted in 52 patients: twenty-six de novo MS patients who start DMF treatment and 26 patients who switch from first-line DMT treatment (interferon, glatiramer acetate, teriflunomide) to treatment with DMF are matched for age and gender. Sample size calculation considers a significance level of 5% and a power of 80% to detect a difference of 0.22 with a standard deviation of 0.5, assuming a patients' loss of 20-30%.

You may qualify if:

• Patients must voluntarily give written informed consent. Patients must read and fully understand the Informed Consent Form (ICF);
• Patient diagnosed with MS according to McDonald criteria;
• Adult patients, males or female patients ≥ 18 years old;
• Relapsing disease course;
• Expanded Disability Status Scale (EDSS) ≤5.5;
• Patients who initiate treatment with DMF 240 mg twice daily according prescribing criteria.

You may not qualify if:

• Diagnosis of non-relapsing MS;
• Use of experimental drug or investigational procedure during the study period;
• Pregnancy;
• Severe hepatic impairment;
• Relapse or corticosteroid use within 30 days prior to baseline MRI scan;
• Previous use of alemtuzumab, cladribine, rituximab, or mitoxantrone.

Sponsors & Collaborators

• IRCCS Centro Neurolesi Bonino Pulejo: lead

Study Sites (1)

IRCCS Centro Neurolesi "Bonino-Pulejo"

Messina, 98124, Italy

Location

MeSH Terms

Conditions

Multiple Sclerosis

Interventions

Dimethyl Fumarate

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Fumarates; Dicarboxylic Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 17, 2023
• First Posted: April 13, 2023
• Study Start: February 24, 2021
• Primary Completion: October 11, 2022
• Study Completion: June 7, 2023
• Last Updated: October 15, 2024

Record last verified: 2024-10

Locations

IT (1)