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The effect of Fampridine-SR on cognitive fatigue in a randomized double-blind crossover trial in patients with MS
Multiple Sclerosis and Related Disorders, Volume 11, January 2017, Pages 4 - 9
Cognitive fatigue (CF) is a common complaint in persons with MS (PwMS). Fampridine-SR improves ambulation, fatigue and endurance, due to enhancing action potential formation by blocking potassium channels in demyelinated axons. Thus, through this same mechanism, it is hypothesized that Fampridine-SR could improve CF.
To determine if Fampridine-SR objectively improves CF in PwMS.
Sixty PwMS of any type with CF, defined as 3 or less correct responses when comparing the last third to the first third on the Paced Auditory Serial Addition Test (PASAT), were recruited from a tertiary care MS clinic in London (ON) Canada. Subjects also had to be between 18 and 64 years of age, inclusive, not had a relapse in the last 60 days or corticosteroids in the last 30 days, EDSS 0.0–7.0, and no other diagnosis that could cause cognitive impairment. A randomized double blind crossover design was used: subjects were randomized to either placebo or Fampridine-SR for 4 weeks, then after at least a one week washout, received the opposite treatment. Subjects were assessed before and after each treatment block. The primary outcome was the PASAT CF score after treatment with Fampridine-SR compared to placebo. T-tests and chi-square were used to compare demographics between the two groups (placebo-Fampridine-SR vs. Fampridine SR-placebo). Treatment effects were assessed using factorial ANOVA, with treatment (Fampridine-SR vs. placebo) and time (before and after treatment) as within-subject variables.
Of the 60 subjects randomized, 48 completed the study; three were removed due to an adverse event while in the treatment arm (one due to relapse while on placebo, one due to urinary retention and one due to dizziness and headache while on Fampridine-SR). The subjects had a mean age of 46.5±10.0 years, education of 13.6±1.9 years, and were diagnosed with MS 10.6±9.6 years ago. The majority were female (46, 76.7%), had relapsing remitting MS (41, 68.3%) with median EDSS of 3.5 (range 1.0–7.0). There were no significant demographic differences between the two groups. The treatment x time interaction within the factorial ANOVA on PASAT CF scores was statistically significant, F(1, 45)=8.28, p=0.006, suggesting there is a difference between the treatments (placebo vs. Fampridine-SR), over the course of the study. An evaluation of the mean scores suggests, however, that subjects saw a greater improvement when they were given the placebo, than when they were given the active medication. Similarly, individuals showed a greater increase in their information processing speed (as measured by the PASAT) over the course of treatment when they were given the placebo, as compared with the active medication F(1,45)=4.17, p=0.047.
Although this small pilot study does not suggest that Fampridine-SR results in a statistically significant improvement of CF in MS patients, as compared to placebo, individuals demonstrated an improvement in both information processing speed and CF, suggesting further studies are warranted.
- Cognitive Fatigue (CF) is a common complaint in persons with MS.
- This trial addressed Fampridine-SR as a potential treatment for CF.
- A cross-over randomized placebo controlled design was used.
- No benefit was seen on measures of CF in persons with MS.
Keywords: Multiple sclerosis, Cognition, Cognitive fatigue, Fampridine-SR.
It is estimated that 43–60% of persons with Multiple Sclerosis (PwMS) have cognitive dysfunction (Benedict et al, 2006 and Rao et al, 1991b) and studies using objective neuropsychological tests have consistently shown impairment in speed of information processing and sustained attention (DeLuca et al, 2004, DeLuca et al, 1998, DeLuca et al, 1994, DeLuca et al, 1993, Demaree et al, 1999, Peyser et al, 1990, Rao, 1989, Rao et al, 1989, and Rao et al, 1984). Further, MS patients complain of “cognitive fatigue”, a symptom that may or may not be associated with generalized/central fatigue. Cognitive fatigue (CF) has been defined as a decline in cognitive performance during a task requiring sustained cognitive activity (Schwid et al., 2003). Although generalized or motor/muscle fatigue has been shown to affect the subjective assessment of cognitive performance, it does not affect performance on objective cognitive measures (Morrow et al, 2009a and Kinsinger et al, 2010). In contrast, cognitive fatigue has been demonstrated in PwMS on objective neuropsychological tests assessing information processing speed or sustained attention (Schwid et al, 2003, Kujala et al, 1995, Krupp, 2000, and Morrow et al, 2015). Currently there are no known treatments for CF in PwMS.
Fampridine-SR (4-aminopyridine) is a slow release oral medication that acts as a selective neuronal potassium-channel blocker. It has been investigated in several MS studies and has been shown to improve ambulation, fatigue and endurance (van Diemen et al, 1992, Bever et al, 1994, Schwid et al, 1997, and Stefoski et al, 1991). The hypothesis for the mode of action of Fampridine-SR in PwMS is based on the fact that demyelinated axons do not effectively conduct action potentials partly due to abnormal potassium currents that contribute to conduction failure by decreasing action potential duration and amplitude. Thus, potassium channel blockers such as 4-aminopyridine or 3,4 di-aminopyridine improve nerve impulse propagation by enhancing action potential formation, improving conduction and preventing conduction block. Based on the proposed mechanism of action of Fampridine-SR, it is possible that it could improve CF in PwMS by improving nerve conduction. Using a placebo controlled cross-over study, the goal of this study was to determine if Fampridine-SR had a beneficial effect on CF in PwMS.
2. Materials and methods
2.1. Study design
This study was a double-blind, placebo controlled, randomized, cross-over trial. Using a computer-based random number generator, equal numbers of subjects were assigned to the treatment and control groups. The treating physician, research associates and subjects were all blinded to treatment assignment; only the pharmacist was unblinded to subject assignment. In block one subjects were assigned to either Fampridine-SR 10 mg BID or matching placebo. The active and placebo capsules were provided by Biogen Idec Canada and were identical; packaging and drug dispensation were provided in identical bottles by our local pharmacist who was unblinded. Subjects remained on the assigned treatment for four weeks, and then stopped. After a minimum one week washout period, subjects entered block two: subjects originally assigned to Fampridine-SR 10 mg BID started matching placebo, while those originally assigned to placebo were assigned to Fampridine-SR 10 mg BID; subjects stayed on these medications for four weeks. Assessments occurred at the beginning and end of both block one and block two.
Subjects were recruited within the London MS clinic, a tertiary care center MS clinic located in London (ON) Canada, from December 2012 to April 2015. Recruitment stopped when the sample size criteria was met, after allowing for a 15% dropout rate. The main criterion for inclusion was evidence of CF on the PASAT, as described below.
2.2.1. Inclusion criteria
Subjects eligible for inclusion in the study were: males or females; 18 years old - 64 years of age, inclusive; capable of understanding and complying with the protocol, including speaking and writing fluent English and having at least a 9th grade education and a visual acuity of 20/70 or better; diagnosed with Relapsing Remitting, Secondary Progressive or Primary Progressive MS, as per revised McDonald's Criteria (Polman et al., 2011); have not received corticosteroids in last thirty (30) days or a relapse in the last sixty (60) days; the subject's MS was considered stable; an Expanded Disability Status Scale (EDSS) (Kurtzke, 1983) of ≤7.0; if female, must neither be pregnant nor breast-feeding.
2.2.2. Exclusion criteria
The following criteria resulted in exclusion from the study: the presence of cognitive deficits caused by concomitant medication usage or other significant neurological/psychological disease such Alzheimer's disease, stroke or vascular dementia or traumatic brain injury; evidence of major depression as determined by a positive Beck Depression Index, Fast Screen (BDIFS) (Benedict et al., 2003) and/or clinician interview; a history of uncontrolled hypertension, tachycardia, or other cardiovascular disease; a history or current presentation of seizure; currently taking compounded 4-aminopyridine or another form of fampridine; a known hypersensitivity to any medical or non-medical ingredient of the medication tablet; evidence of renal impairment (creatinine clearance ≤80 mL/min) as per Health Canada requirements; or taking medications that are inhibitors of the renal organic cation transporter-2. Subjects could remain on any other medications that have been at a stable dose for ≥28 days prior to enrollment in the study.
At the time of enrollment, subjects were interviewed and charts were reviewed to collect the following information: type of MS, years since MS diagnosis, education in years, EDSS score, date of last relapse and time since last corticosteroids administration if applicable, age, gender, ethnicity, medications including disease modifying medications for MS, other medical conditions. At each contact (at the end of block one, and the start and end of block two) this information was reviewed, as well as inclusion/exclusion criteria. Subjects who withdrew consent, experienced a relapse during the course of the trial, or had a severe adverse event warranting unbinding and/or medication discontinuation were removed from the study.
2.3.2. Cognitive fatigue
A CF measure using the Paced Auditory Serial Addition Test (PASAT) (Gronwall, 1977) was the primary outcome (Morrow et al., 2015). Briefly, Rao's adaptation (Rao et al, 1991b, Rao et al, 1991a, Rao, 1991a, and Rao, 1991b) of the PASAT is an auditory test of attention and processing speed in which subjects listen to single digit numbers voiced every three seconds. The subject responds with the sum of the last two digits presented. As each new number is presented, the subject must disregard the previous response, recall the last two digits and respond with the new sum. There are 60 stimuli in total. The PASAT CF score is calculated as the number of correct responses in the last third (last 20 responses) minus the number of correct responses in the first third (first 20 responses) of the PASAT. CF was considered present if the CF PASAT score was −3 or less, meaning the subject voiced at least 3 fewer correct responses in the last 3rd of the PASAT compared to the 1st third (Morrow et al., 2015).
2.4. Statistical treatment
2.4.1. Statistical analysis
In order to compare the demographics between the two groups (placebo/Fampridine-SR vs. Fampridine-SR/placebo) and ensure randomization was effective, t-tests and chi-square were used as appropriate. Two factorial ANOVAs were conducted (one for the raw PASAT score, and second analysis of the PASAT CF score). Both of these ANOVAs included three independent variables (order in which the participant received the placebo or the active drug, pre-test vs. post-test, and placebo vs. active drug).
2.4.2. Sample size
We could find no prior data on the treatment of CF that provided data that could be used to estimate exact effect size for this study. Accordingly, we estimated an effect size estimate using Cohen's (1988) guidelines (Cohen, 1988). We adopted an effect size of 0.25 (a “medium to large effect”), as Cohen suggested that this magnitude of effect should be visible with the careful attention of an untrained observer, using no sophisticated equipment, and should therefore be clinically significant. We used routines within the “pwr” library in R (CS, 2015), and determined that a sample size of 51 would be needed in order to identify a statistically significant effect with an alpha of 0.05, and a power of 0.90. Allowing for a dropout rate of 15%, this suggests that we needed to sample approximately 59 participants, in order to be reasonably assured that we would finish the study with an adequate sample size.
2.4.3. Trial registration, ethics and sponsorship
This study was registered with clinicaltrials.gov, NCT01667497, and was reviewed and approved by the University of Western Ontario's Health Sciences Ethics Review Board (HSREB). This study was sponsored by an investigator initiated trial (IIT) grant from Biogen Idec Canada who reviewed the protocol and provided both Fampridine-SR and matching placebo. Biogen Idec Canada nor any of its representatives had any role in study implementation or recruitment and did not have access to the data or the statistical analysis.
In total, 94 potential subjects were screened for study participation (Fig. 1). The main reasons for exclusion were no evidence of cognitive fatigue (n=28) or met exclusion criteria (n=3). Sixty (60) subjects signed informed consent to participate in this study. The included cohort had 46 (76.7%) females, had an average age of 46.5±10.0 years, and completed 13.6±1.9 years of formal education. Additionally, the cohort was mostly relapsing remitting MS (41, 68.3%), had MS for 10.6±9.6 years, and had a median EDSS of 3.5 (1.0–7.0). Just over half the sample (52.7%) were on a disease modifying therapy.
Fampridine-SR Enrollment Flow Diagram.
Randomization resulted in 31 subjects assigned to placebo in block one, 29 to Fampridine-SR in block one. Of these subjects, there were no significant differences between the two groups (see Table 1). Two subjects were removed after randomization due to lack of CF on PASAT at visit 1 (both assigned to placebo in block one). Three subjects were removed from the study due to serious adverse events. One subject experience a relapse while on the placebo treatment (block one); and one subject experience dizziness, headache and leg weakness while on fampridine-SR (block one). One subject presented to the emergency department with urinary retention 4 days after starting block two; the treatment assignment was unblinded and he was on Fampridine-SR at that time. In block one, 6 subjects (three currently assigned to placebo, three currently assigned to drug) withdrew consent; no reason was the withdrawal was given. One other subject completed block one (assigned to Fampridine-SR) but withdrew consent prior to commencing block two (See Fig. 1).
Baseline characteristics of subjects randomized to placeblo or Fampridine-SR in block one.
|Characteristic||Placebo (n=31)||Fampridine-SR (n=29)||p-value|
|Age in years|
|Years since diagnosis|
|Education in years|
|Gender N (%)|
|Female||23 (74.2)||23 (77.3)||0.64+|
|Ethnicity N (%)|
|Caucasian||30 (96.8)||27 (93.1)||0.51+|
|MS type N (%)|
|RRMS||24 (77.4)||17 (58.6)||0.20+|
|SPMS||6 (14.4)||8 (27.6)|
|PPMS||1 (3.2)||4 (13.8)|
|On DMT n (%)||21 (67.7%)||11 (37.9%)||0.08+|
|Median (Range)||3.0 (1.5–6.5)||3.5 (1.0–7.0)||0.64|
* t-test; +chi-square.
N: number; SD: standard deviation; RRMS: relapsing remitting multiple sclerosis; SPMS: secondary progressive MS; PPMS: primary progressive MS; DMT: disease modifying therapy; EDSS Expanded Disability Status Scale
3.2. PASAT and PASAT CF scores
At the baseline (pre-block) assessment prior to starting placebo, the PASAT score was 38.0±10.7 and the PASAT CF score was −5.3±1.9; prior to starting Fampridine SR, the PASAT score was 44.9±11.0 and the PASAT CF score was −3.3±2.7. After 4 weeks (post-block) on placebo, the PASAT score was 42.8±10.5 and the PASAT CF score was −2.2±2.8, while after 4 weeks on Fampridine SR, the PASAT score was 46.7±10.3 and the PASAT CF score was −2.2±2.7 (Table 2 and Table 3).
PASAT CF scores before and after treatment with either placebo or Fampridine-SR.
|Visit||PASAT CF – placebo||PASAT CF – Fampridine-SR|
|Baseline (pre-block 1 or 2)||−5.3±1.9||−3.3±2.7|
|Treatment (post-block 1 or 2)||−2.2±2.8||−2.2±2.7|
PASAT scores before and after treatment with either placebo or Fampridine-SR.
|Baseline block 1 or 3||38.0±10.7||44.9±11.0|
|Post- treatment block 2 or 4||42.8±10.5||46.7±10.3|
3.3. Treatment effect
Analysis of the PASAT CF variable suggested that there was no statistically significant main effect of randomization order on the model, nor did randomization order interact with any of the independent variables. The treatment x time interaction was, however, statistically significant, F (1, 45)=8.28, p=0.006, suggesting that there is a significant difference between the placebo and treatment conditions. Similar results were found with the PASAT raw score, insofar as there was no statistically significant effect of randomization order on the model, and there was a statistically significant treatment x time interaction, F (1, 45)=4.17, p=0.047. Evaluation of the means, however, for both the PASAT CF variable and the PASAT raw scores, suggests that subjects saw a greater improvement while on placebo, than when they were given the active medication (see Table 4 and Fig. 2).
PASAT CF scores before and after each block, with either placebo or Fampridine-SR.
|Visit||PASAT CF – placebo||PASAT CF – Fampridine-SR|
|Visit 1 – Baseline block 1||−5.4±1.9||−5.3±1.9|
|Visit 2 – End of block 1||−2.2±3.3||−2.2±2.2|
|Visit 3 – Baseline block 2||−4.0±2.6||−2.7±2.6|
|Visit 4 – End of block 2||−2.4±2.4||−2.0±3.0|
Mean and standard deviation of PASAT CF score while on placebo or Fampridine-SR, before and after the treatment block.
This is the first study to directly address the treatment of cognitive fatigue, a commonly reported symptom in persons with MS; Fampridine-SR did not meet the primary objective, which was to improve (i.e., decrease) cognitive fatigue as measured on the PASAT.
Cognitive fatigue has been defined as a decline in cognitive performance during a task requiring sustained cognitive activity, which can be demonstrated with a decline in performance over time (Schwid et al., 2003). Generalized fatigue, a symptom that is also common in PwMS, is a subjective sensation of fatigue as reported by the patient, and is different from CF. Generalized fatigue has been shown to affect the subjective assessment of cognitive performance, while it does not affect performance on objective cognitive measures (Kinsinger et al, 2010 and Morrow et al, 2009b). In contrast, CF is both a subjective sensation of worsening performance over time, and has been demonstrated in PwMS on objective neuropsychological tests, specifically those assessing processing speed such as the PASAT. When compared to normal controls, PwMS are less likely to maintain performance on measures of processing speed over time. More specifically, the PASAT has been shown to be a reliable and sensitive marker of CF in PwMS when comparing speed at the end of the task to the speed at the beginning of the task. Schwid et al. (2003) examined the decline in performance on the PASAT in PwMS compared to normal controls. There was a 5.3–5.8% decline in correct responses when comparing the MS subjects’ performance at the beginning vs. the end of the test. Normal controls did not show a significant decrease in performance (Schwid et al., 2003). Bryant et al. (2004) compared MS subjects performance on the 2nd half of the PASAT to the first half and found a consistent decline in the number of correct responses over time (Bryant et al., 2004). Walker et al. (2013) also demonstrated that PwMS were more susceptible to CF on the PASAT than normal controls when comparing the 1st half to the last half of the PASAT and this worsening correlated with the “cognitive dimension” of the Fatigue Impact Scale (FIS) (Walker et al., 2013).
Although CF is common in PwMS, there are, currently, no effective treatments for this debilitating symptom. As previously mentioned, it is hypothesized that the mode of action of Fampridine-SR is by improving nerve impulse propagation via enhanced action potential formation (Shi et al, 1997 and Blight, 1989). Based on this proposed mechanism of action, it was proposed that Fampridine-SR would improve CF in PwMS by improving nerve conduction. Two previous studies have addressed the effect of aminopyridines on cognition in PwMS. Both studies were negative; no benefit was found. However, in the first study, the primary aim of the study was to examine changes in generalized fatigue and the cognitive outcomes were tertiary outcomes only (Rossini et al., 2001). In the other study, performance on Rao's Brief Repeatable Neuropsychological Battery (BRN-B) before and after treatment with 4-aminopyridine was compared. A trend was found for improvement on measures of verbal learning and on the PASAT 2.0 s version, but the findings were not statistically significant (Smits et al., 1994). However the trial only had 20 subjects and thus both of these studies were underpowered.
There are a few weaknesses to this study that may have influenced the results. It had a small study administered at only one site. It is possible that this study was underpowered due to the small sample size; there was no previous data to allow us to properly calculate a sample size. Further, in the previous studies involving Fampridine-SR, a notable responder effect was noted, meaning some PwMS in the study responded very well based on the timed walk, while others do not show any beneficial response (Goodman et al., 2009). It is possible there is a similar issue in terms of CF. Further, we did not use a self-reported measure of CF, such as the FIS, that could have identified potential responders, nor was a full cognitive assessment done at baseline. Finally, this study demonstrated a significant practice effect of the PASAT, a known limitation of this test (Barker-Collo, 2005). Thus, as demonstrated in Table 4, many PwMS entering block two no longer met criteria for CF, which would have negatively affected the study.
Overall, this small cross-over study does not support the use of Fampridine-SR to treat cognitive fatigue in PwMS. Further studies are needed to address potential treatment options for this common MS symptom.
Conflict of interest/role of funding source
This study was sponsored by investigator initiated trial (IIT) grant from Biogen Idec Canada (Grant no. CAN-FMP-12-10337). The administration of the study and data analysis was done without any input from any Biogen Idec representative.
There are no other conflicts to report for any author.
This trial was registered with clinicaltrials.gov: NCT01667497. This study was sponsored by investigator initiated trial (IIT) grant from Biogen Idec Canada.
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a London Health Sciences Center, London, Ontario, Canada
b University of Western Ontario, Department of Clinical Neurological Sciences, Western University, 339 Windermere Road, London, Ontario, Canada, N6A 5A5
c University of Western Ontario, Department of Health and Rehabilitation Sciences, Western University, London, Ontario, Canada
⁎ Corresponding author at: London Health Sciences Center, London, Ontario, Canada.
☆ This trial was registered with clinicaltrials.gov, NCT01667497. This study was sponsored by investigator initiated trial (IIT) grant from Biogen Idec Canada.
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