This prospective monocentric open label trial was realized in the Laboratory of Clinical Functional Exploration of Movement at the University Hospital of Besancon. Cognitive evaluations: 7 days before fampridine treatment initiation (Pre 1), on the day of fampridine treatment initiation (Pre 2), 14 and 21 days after fampridine treatment initiation, respectively Post 1 and Post 2. Gait evaluations were assessed at Pre 1, Pre 2 and Post 1. Fampridine was prescribed according to guidelines issued by the French Health Products Safety Agency at the dose of 10 mg twice daily. Fampridine is indicated for the improvement of walking in MS patients with a walking disability (EDSS 4-6.5). A walking test is recommended to evaluate improvement after 2 weeks of treatment. According to the practitioner evaluation between Pre 2 and Post 1 (i.e. before and after fampridine treatment), patients were classified into 2 groups: responders whose clinical status was improved and non-responders whose clinical status was not improved.
Multiple sclerosis (MS) is a chronic neurological disorder affecting young and middle-aged adults with a female to male ratio of more than 3:1. The cause of MS is unknown although it involves genetic susceptibility and environmental exposure. Since there is no known cure for MS, the main goals of treatment is to delay progression of the disease and to improve health-related quality of life (HRQoL) by masking patients' symptoms. Among several symptoms of MS (e.g., motor and cognitive impairments, optic neuritis, fatigue, pain, urinary dysfunction), gait impairment, defined as an activity limitation by the International Classification of Functioning Disability and Health, is one of the most common and disabling dysfunction in Persons with Multiple Sclerosis PwMS. Studies have reported that approximately 75 % of individuals with MS experience clinically significant walking disturbances. Likewise, fatigue, impairment of information-processing speed (IPS), attention, working memory and executive functions can occur in MS and can worsen during the evolution of the disease. Studies have shown that MS symptomatic treatment by fampridine (4-aminopyridine) is associated with improvements in walking and muscle strength and possibly with cognition, vision, fatigue and spasticity. Indeed, fampridine is a potassium channel blocker which reduces the leakage of ionic current through these channels, prolonging repolarization and thus, enhancing action-potential formation in demyelinated axons. Presumably, by enhancing action-potential formation, more impulses might be conducted in the central nervous system (CNS) and neurological functions could be ameliorated. In recent phase III studies, Goodman et al. investigated the fampridine effect on the walk of individuals with MS during a timed 25-foot walk test (T25FW). Improvement in walking velocity (≈25 % from baseline) was found for 35-43 % of the individuals in the interventional group. However, improvement in neuronal conduction induced by fampridine might not be limited to short distances of gait or even to motor functions and might also improve long distance ambulation or cognitive functions. Different assessments have been used for measuring gait impairments in multiple sclerosis, including the Timed 25-Foot Walk (T25FW), Six-Minute Walk Test (6MWT), spatio-temporal gait parameters measured with an instrumented walkway or the Timed Up and Go test (TUG). These different assessments can be performed at different conditions: simple task, fast speed or dual task. In this last case, the gait is associated with a cognitive or another motor task. For cognitive assessments, Symbol Digit Modalities Test (SDMT) and verbal fluencies have been used in previous studies. The aimed of the study was to evaluate the impact of fampridine in gait evaluating by long distance tests and to evaluate the impact of fampridine in fatigue and cognition. Assessments of patients were performed 7 days before fampridine treatment initiation (Pre 1), on the day of fampridine treatment initiation (Pre 2), 14 and 21 days after fampridine treatment initiation, respectively Post 1 and Post 2. Gait evaluations were assessed at Pre 1, Pre 2 and Post 1. The first two assessments were intended to evaluate the variability of measurement without any treatment. A measurement of activity was performed by accelerometer during the period covering the first two assessments. The third assessment was intend to measure clinical improvements. The fourth seeks to show a potentially delayed action of fampridine on cognition.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
89
Oral intake of 10 mg twice daily
CHU Jean Minjoz
Besançon, France
6 Minute Walk Test (6MWT)
The 6MWT assessed the submaximal level of functional capacity. It was realized according to the recommendation of the American Thoracic Society. 6MWT instructions were read prior to each walk. Participants used his/her typical assistive device and walked around a circuit with 24-meters longer. If necessary, they were allowed to have a rest period and encouragement phrases were used each 30 seconds.
Time frame: Timed 21 days
Verbal fluencies
Both semantic and phonological verbal fluencies were assessed in a quiet room. Semantic fluency was measured by asking patients to provide as many animal names as possible in 120 s. Different kinds of one sort of animal were accepted (e.g. kinds of birds or fish). Phonological fluency was measured by asking patients to provide as many words as possible beginning with the letter 'P' in 120 s. They were informed that proper nouns and words with the same stem would not be counted (e.g. pen, pencil). Patients were instructed to avoid repetitions.
Time frame: Day 1
Verbal fluencies
Both semantic and phonological verbal fluencies were assessed in a quiet room. Semantic fluency was measured by asking patients to provide as many animal names as possible in 120 s. Different kinds of one sort of animal were accepted (e.g. kinds of birds or fish). Phonological fluency was measured by asking patients to provide as many words as possible beginning with the letter 'P' in 120 s. They were informed that proper nouns and words with the same stem would not be counted (e.g. pen, pencil). Patients were instructed to avoid repetitions.
Time frame: 7 days
Verbal fluencies
Both semantic and phonological verbal fluencies were assessed in a quiet room. Semantic fluency was measured by asking patients to provide as many animal names as possible in 120 s. Different kinds of one sort of animal were accepted (e.g. kinds of birds or fish). Phonological fluency was measured by asking patients to provide as many words as possible beginning with the letter 'P' in 120 s. They were informed that proper nouns and words with the same stem would not be counted (e.g. pen, pencil). Patients were instructed to avoid repetitions.
Time frame: 21 days
Verbal fluencies
Both semantic and phonological verbal fluencies were assessed in a quiet room. Semantic fluency was measured by asking patients to provide as many animal names as possible in 120 s. Different kinds of one sort of animal were accepted (e.g. kinds of birds or fish). Phonological fluency was measured by asking patients to provide as many words as possible beginning with the letter 'P' in 120 s. They were informed that proper nouns and words with the same stem would not be counted (e.g. pen, pencil). Patients were instructed to avoid repetitions.
Time frame: 28 days
Verbal fluencies
Both semantic and phonological verbal fluencies were assessed in a quiet room. Semantic fluency was measured by asking patients to provide as many animal names as possible in 120 s. Different kinds of one sort of animal were accepted (e.g. kinds of birds or fish). Phonological fluency was measured by asking patients to provide as many words as possible beginning with the letter 'P' in 120 s. They were informed that proper nouns and words with the same stem would not be counted (e.g. pen, pencil). Patients were instructed to avoid repetitions.
Time frame: up to one year
Symbol Digit Modalities Test
The SDMT has a key at the top of the page with numbers and symbols; participants are required to refer to the key to correctly decode several lines of symbols. After completing sample items correctly, participants are timed for 90 s and the total number correct is their raw score. Only correct answers were account to the final score.
Time frame: Day 1
Symbol Digit Modalities Test
The SDMT has a key at the top of the page with numbers and symbols; participants are required to refer to the key to correctly decode several lines of symbols. After completing sample items correctly, participants are timed for 90 s and the total number correct is their raw score. Only correct answers were account to the final score.
Time frame: 7 days
Symbol Digit Modalities Test
The SDMT has a key at the top of the page with numbers and symbols; participants are required to refer to the key to correctly decode several lines of symbols. After completing sample items correctly, participants are timed for 90 s and the total number correct is their raw score. Only correct answers were account to the final score.
Time frame: 21 days
Symbol Digit Modalities Test
The SDMT has a key at the top of the page with numbers and symbols; participants are required to refer to the key to correctly decode several lines of symbols. After completing sample items correctly, participants are timed for 90 s and the total number correct is their raw score. Only correct answers were account to the final score.
Time frame: 28 days
Symbol Digit Modalities Test
The SDMT has a key at the top of the page with numbers and symbols; participants are required to refer to the key to correctly decode several lines of symbols. After completing sample items correctly, participants are timed for 90 s and the total number correct is their raw score. Only correct answers were account to the final score.
Time frame: up to one year
Modified Fatigue Impact Scale (mFIS)
The FIS is a 40-item Standardized questionnaire validated for MS. For our study, we used the validated French version of the FIS in MS, called "EMIF-SEP". The EMIF-SEP is composed of 40 items organized into four dimensions (cognitive, physical, social role and psychological dimensions) with each items rated on a four point scale (4=it's always true, 3=it's sometimes true, 2=it's sometimes false, 1=it's always false) and the total fatigue scores are standardized from 0 (meaning no fatigue) to 100 (meaning high degree of fatigue). The forty items are divided into the four dimensions: cognitive (10 items), physical (14 items), social role (13 items) and psychological (4 items). Each dimension score was also standardized as a percentage like total score.
Time frame: day 1
Modified Fatigue Impact Scale (mFIS)
The FIS is a 40-item Standardized questionnaire validated for MS. For our study, we used the validated French version of the FIS in MS, called "EMIF-SEP". The EMIF-SEP is composed of 40 items organized into four dimensions (cognitive, physical, social role and psychological dimensions) with each items rated on a four point scale (4=it's always true, 3=it's sometimes true, 2=it's sometimes false, 1=it's always false) and the total fatigue scores are standardized from 0 (meaning no fatigue) to 100 (meaning high degree of fatigue). The forty items are divided into the four dimensions: cognitive (10 items), physical (14 items), social role (13 items) and psychological (4 items). Each dimension score was also standardized as a percentage like total score.
Time frame: 7 days
Modified Fatigue Impact Scale (mFIS)
The FIS is a 40-item Standardized questionnaire validated for MS. For our study, we used the validated French version of the FIS in MS, called "EMIF-SEP". The EMIF-SEP is composed of 40 items organized into four dimensions (cognitive, physical, social role and psychological dimensions) with each items rated on a four point scale (4=it's always true, 3=it's sometimes true, 2=it's sometimes false, 1=it's always false) and the total fatigue scores are standardized from 0 (meaning no fatigue) to 100 (meaning high degree of fatigue). The forty items are divided into the four dimensions: cognitive (10 items), physical (14 items), social role (13 items) and psychological (4 items). Each dimension score was also standardized as a percentage like total score.
Time frame: 21 days
Modified Fatigue Impact Scale (mFIS)
The FIS is a 40-item Standardized questionnaire validated for MS. For our study, we used the validated French version of the FIS in MS, called "EMIF-SEP". The EMIF-SEP is composed of 40 items organized into four dimensions (cognitive, physical, social role and psychological dimensions) with each items rated on a four point scale (4=it's always true, 3=it's sometimes true, 2=it's sometimes false, 1=it's always false) and the total fatigue scores are standardized from 0 (meaning no fatigue) to 100 (meaning high degree of fatigue). The forty items are divided into the four dimensions: cognitive (10 items), physical (14 items), social role (13 items) and psychological (4 items). Each dimension score was also standardized as a percentage like total score.
Time frame: 28 days
Modified Fatigue Impact Scale (mFIS)
The FIS is a 40-item Standardized questionnaire validated for MS. For our study, we used the validated French version of the FIS in MS, called "EMIF-SEP". The EMIF-SEP is composed of 40 items organized into four dimensions (cognitive, physical, social role and psychological dimensions) with each items rated on a four point scale (4=it's always true, 3=it's sometimes true, 2=it's sometimes false, 1=it's always false) and the total fatigue scores are standardized from 0 (meaning no fatigue) to 100 (meaning high degree of fatigue). The forty items are divided into the four dimensions: cognitive (10 items), physical (14 items), social role (13 items) and psychological (4 items). Each dimension score was also standardized as a percentage like total score.
Time frame: up to one year
Fatigue Severity Scale (FSS)
The FSS is a method of evaluating fatigue in PwMS and other conditions, including chronic fatigue immune dysfunction syndrome and systemic lupus erythematosus. The FSS is designed to differentiate fatigue from clinical depression because both share some of the same symptoms. The FSS questionnaire is composed of 9 statements related to patients' subjective perception of fatigue and its consequences on everyday activities. Patients are asked to rate their level of agreement (toward 7) or disagreement (toward 0) with the 9 statements.
Time frame: day 1
Fatigue Severity Scale (FSS)
The FSS is a method of evaluating fatigue in PwMS and other conditions, including chronic fatigue immune dysfunction syndrome and systemic lupus erythematosus. The FSS is designed to differentiate fatigue from clinical depression because both share some of the same symptoms. The FSS questionnaire is composed of 9 statements related to patients' subjective perception of fatigue and its consequences on everyday activities. Patients are asked to rate their level of agreement (toward 7) or disagreement (toward 0) with the 9 statements.
Time frame: 7 days
Fatigue Severity Scale (FSS)
The FSS is a method of evaluating fatigue in PwMS and other conditions, including chronic fatigue immune dysfunction syndrome and systemic lupus erythematosus. The FSS is designed to differentiate fatigue from clinical depression because both share some of the same symptoms. The FSS questionnaire is composed of 9 statements related to patients' subjective perception of fatigue and its consequences on everyday activities. Patients are asked to rate their level of agreement (toward 7) or disagreement (toward 0) with the 9 statements.
Time frame: 21 days
Fatigue Severity Scale (FSS)
The FSS is a method of evaluating fatigue in PwMS and other conditions, including chronic fatigue immune dysfunction syndrome and systemic lupus erythematosus. The FSS is designed to differentiate fatigue from clinical depression because both share some of the same symptoms. The FSS questionnaire is composed of 9 statements related to patients' subjective perception of fatigue and its consequences on everyday activities. Patients are asked to rate their level of agreement (toward 7) or disagreement (toward 0) with the 9 statements.
Time frame: 28 days
Fatigue Severity Scale (FSS)
The FSS is a method of evaluating fatigue in PwMS and other conditions, including chronic fatigue immune dysfunction syndrome and systemic lupus erythematosus. The FSS is designed to differentiate fatigue from clinical depression because both share some of the same symptoms. The FSS questionnaire is composed of 9 statements related to patients' subjective perception of fatigue and its consequences on everyday activities. Patients are asked to rate their level of agreement (toward 7) or disagreement (toward 0) with the 9 statements.
Time frame: up to one year
Multiple Sclerosis Walking Scale 12 (MSWS12)
The original scoring provides options 1-5 for each item, with 1 meaning no limitation and 5 meaning extreme limitation on the gait-related item.
Time frame: day 1
Multiple Sclerosis Walking Scale 12 (MSWS12)
The original scoring provides options 1-5 for each item, with 1 meaning no limitation and 5 meaning extreme limitation on the gait-related item.
Time frame: 7 days
Multiple Sclerosis Walking Scale 12 (MSWS12)
The original scoring provides options 1-5 for each item, with 1 meaning no limitation and 5 meaning extreme limitation on the gait-related item.
Time frame: 21 days
Multiple Sclerosis Walking Scale 12 (MSWS12)
The original scoring provides options 1-5 for each item, with 1 meaning no limitation and 5 meaning extreme limitation on the gait-related item.
Time frame: 28 days
Multiple Sclerosis Walking Scale 12 (MSWS12)
The original scoring provides options 1-5 for each item, with 1 meaning no limitation and 5 meaning extreme limitation on the gait-related item.
Time frame: up to one year
"PERception de la Sclérose En Plaques et de ses Poussées" (PERSEPP)
The PERSEPP scale was used to evaluate the HRQoL of patients with MS (Baroin et al. 2013). This scale takes into account several aspects of HRQoL distributed across 66 items (described below) and includes relapse phases. Each item contains 6 response types according to a Likert scale where "0" was "strongly disagree" and "5" was "strongly agree". The PERSEPP scale has been validated in the French language
Time frame: day 1
"PERception de la Sclérose En Plaques et de ses Poussées" (PERSEPP)
The PERSEPP scale was used to evaluate the HRQoL of patients with MS (Baroin et al. 2013). This scale takes into account several aspects of HRQoL distributed across 66 items (described below) and includes relapse phases. Each item contains 6 response types according to a Likert scale where "0" was "strongly disagree" and "5" was "strongly agree". The PERSEPP scale has been validated in the French language
Time frame: day 7
"PERception de la Sclérose En Plaques et de ses Poussées" (PERSEPP)
The PERSEPP scale was used to evaluate the HRQoL of patients with MS (Baroin et al. 2013). This scale takes into account several aspects of HRQoL distributed across 66 items (described below) and includes relapse phases. Each item contains 6 response types according to a Likert scale where "0" was "strongly disagree" and "5" was "strongly agree". The PERSEPP scale has been validated in the French language
Time frame: day 21
"PERception de la Sclérose En Plaques et de ses Poussées" (PERSEPP)
The PERSEPP scale was used to evaluate the HRQoL of patients with MS (Baroin et al. 2013). This scale takes into account several aspects of HRQoL distributed across 66 items (described below) and includes relapse phases. Each item contains 6 response types according to a Likert scale where "0" was "strongly disagree" and "5" was "strongly agree". The PERSEPP scale has been validated in the French language
Time frame: day 28
"PERception de la Sclérose En Plaques et de ses Poussées" (PERSEPP)
The PERSEPP scale was used to evaluate the HRQoL of patients with MS (Baroin et al. 2013). This scale takes into account several aspects of HRQoL distributed across 66 items (described below) and includes relapse phases. Each item contains 6 response types according to a Likert scale where "0" was "strongly disagree" and "5" was "strongly agree". The PERSEPP scale has been validated in the French language
Time frame: up to one year
Physical activity in real life condition
The physical activity in real-life condition was measured with an ActiGraph, model wGT3X (Actigraph corp, USA), consistent with previous research on validating accelerometer output in PwMS. The accelerometer was sampled at 30 Hz and values were expressed as number of counts per minute. Participants were instructed to wear the accelerometer on an elastic belt around the waist (i.e. near to the center of displacement of body mass) located above the hip at the non-dominant side ; to wear it for a 7-day period (including a weekend); and to wear it for the whole day from getting out of bed in the morning until getting into bed in the evening. These instructions were summarized in a memo and given to participants.
Time frame: During 7 days (day 1 to day 7)
Physical activity in real life condition
The physical activity in real-life condition was measured with an ActiGraph, model wGT3X (Actigraph corp, USA), consistent with previous research on validating accelerometer output in PwMS. The accelerometer was sampled at 30 Hz and values were expressed as number of counts per minute. Participants were instructed to wear the accelerometer on an elastic belt around the waist (i.e. near to the center of displacement of body mass) located above the hip at the non-dominant side ; to wear it for a 7-day period (including a weekend); and to wear it for the whole day from getting out of bed in the morning until getting into bed in the evening. These instructions were summarized in a memo and given to participants.
Time frame: During 7 days (day 21 to day 28)
Timed 25 Walk Test (T25WT)
According with the recommendation of Cutter et al., participants were asked to walk on a 25 feet (7.62 m) distance. After appropriate instructions and familiarization, participants were asked to perform three gait tasks: walking at their self-selected comfortable speed .
Time frame: Day 1
Timed 25 Walk Test (T25WT)
According with the recommendation of Cutter et al., participants were asked to walk on a 25 feet (7.62 m) distance. After appropriate instructions and familiarization, participants were asked to perform three gait tasks: walking at their self-selected comfortable speed .
Time frame: 7 days
Timed 25 Walk Test (T25WT)
According with the recommendation of Cutter et al., participants were asked to walk on a 25 feet (7.62 m) distance. After appropriate instructions and familiarization, participants were asked to perform three gait tasks: walking at their self-selected comfortable speed .
Time frame: 21 days
Timed 25 Walk Test (T25WT)
According with the recommendation of Cutter et al., participants were asked to walk on a 25 feet (7.62 m) distance. After appropriate instructions and familiarization, participants were asked to perform three gait tasks: walking at their self-selected comfortable speed .
Time frame: 28 days
Timed 25 Walk Test (T25WT)
According with the recommendation of Cutter et al., participants were asked to walk on a 25 feet (7.62 m) distance. After appropriate instructions and familiarization, participants were asked to perform three gait tasks: walking at their self-selected comfortable speed .
Time frame: up to one year
Timed Up and Go test (TUG)
The TUG is a clinical test to assess the level of gait and balance. For its realization, a 47-cm-high chair with arm- and backrest was used. The 3-meters distance was marked with a tape on the floor and a cone marked the turning point. Participants were instructed to get up from the chair, walk 3 meters, turn around the cone and come back to sit on the chair. Participants were encouraged to walk as quickly as possible with safety consistency. After a familiarization trial, the TUG was performed twice. A third trial was applied if a difference of 10% was found between the two first trials. The mean value computed from the two closest trials was taken into account.
Time frame: Day 1
Timed Up and Go test (TUG)
The TUG is a clinical test to assess the level of gait and balance. For its realization, a 47-cm-high chair with arm- and backrest was used. The 3-meters distance was marked with a tape on the floor and a cone marked the turning point. Participants were instructed to get up from the chair, walk 3 meters, turn around the cone and come back to sit on the chair. Participants were encouraged to walk as quickly as possible with safety consistency. After a familiarization trial, the TUG was performed twice. A third trial was applied if a difference of 10% was found between the two first trials. The mean value computed from the two closest trials was taken into account.
Time frame: 7 days
Timed Up and Go test (TUG)
The TUG is a clinical test to assess the level of gait and balance. For its realization, a 47-cm-high chair with arm- and backrest was used. The 3-meters distance was marked with a tape on the floor and a cone marked the turning point. Participants were instructed to get up from the chair, walk 3 meters, turn around the cone and come back to sit on the chair. Participants were encouraged to walk as quickly as possible with safety consistency. After a familiarization trial, the TUG was performed twice. A third trial was applied if a difference of 10% was found between the two first trials. The mean value computed from the two closest trials was taken into account.
Time frame: 21
Timed Up and Go test (TUG)
The TUG is a clinical test to assess the level of gait and balance. For its realization, a 47-cm-high chair with arm- and backrest was used. The 3-meters distance was marked with a tape on the floor and a cone marked the turning point. Participants were instructed to get up from the chair, walk 3 meters, turn around the cone and come back to sit on the chair. Participants were encouraged to walk as quickly as possible with safety consistency. After a familiarization trial, the TUG was performed twice. A third trial was applied if a difference of 10% was found between the two first trials. The mean value computed from the two closest trials was taken into account.
Time frame: 28 days
Timed Up and Go test (TUG)
The TUG is a clinical test to assess the level of gait and balance. For its realization, a 47-cm-high chair with arm- and backrest was used. The 3-meters distance was marked with a tape on the floor and a cone marked the turning point. Participants were instructed to get up from the chair, walk 3 meters, turn around the cone and come back to sit on the chair. Participants were encouraged to walk as quickly as possible with safety consistency. After a familiarization trial, the TUG was performed twice. A third trial was applied if a difference of 10% was found between the two first trials. The mean value computed from the two closest trials was taken into account.
Time frame: up to one year
6 Minute Walk Test (6MWT)
The 6MWT assessed the submaximal level of functional capacity. It was realized according to the recommendation of the American Thoracic Society. 6MWT instructions were read prior to each walk. Participants used his/her typical assistive device and walked around a circuit with 24-meters longer. If necessary, they were allowed to have a rest period and encouragement phrases were used each 30 seconds.
Time frame: day 1
6 Minute Walk Test (6MWT)
The 6MWT assessed the submaximal level of functional capacity. It was realized according to the recommendation of the American Thoracic Society. 6MWT instructions were read prior to each walk. Participants used his/her typical assistive device and walked around a circuit with 24-meters longer. If necessary, they were allowed to have a rest period and encouragement phrases were used each 30 seconds.
Time frame: day 7
6 Minute Walk Test (6MWT)
The 6MWT assessed the submaximal level of functional capacity. It was realized according to the recommendation of the American Thoracic Society. 6MWT instructions were read prior to each walk. Participants used his/her typical assistive device and walked around a circuit with 24-meters longer. If necessary, they were allowed to have a rest period and encouragement phrases were used each 30 seconds.
Time frame: day 28
6 Minute Walk Test (6MWT)
The 6MWT assessed the submaximal level of functional capacity. It was realized according to the recommendation of the American Thoracic Society. 6MWT instructions were read prior to each walk. Participants used his/her typical assistive device and walked around a circuit with 24-meters longer. If necessary, they were allowed to have a rest period and encouragement phrases were used each 30 seconds.
Time frame: up to one year
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