ABSTRACT
Background and Aims
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is an immune‐mediated neuropathy that may cause persistent disability despite immunoglobulin treatment. Ion channel dysfunction has been demonstrated in CIDP, but no therapies specifically target this mechanism. We investigated whether fampridine improves clinical function and electrophysiological measures in CIDP patients with residual symptoms.
Methods
In this two‐center, randomized, double‐blind, placebo‐controlled crossover trial, patients with CIDP receiving stable subcutaneous or intravenous immunoglobulin were assigned to 4 weeks of fampridine (10 mg twice daily) or placebo, separated by a washout period. Co‐primary outcomes were changes in Six‐Spot‐Step Test (SSST) and Nine‐Hole Peg Test (9‐HPT). Secondary outcomes included clinical scores, patient‐reported outcomes, nerve conduction studies, and nerve excitability testing.
Results
Twenty‐eight patients were included in the study. No significant differences were observed between fampridine and placebo for SSST (p = 0.154) or 9‐HPT (p = 0.857). Grip strength and R‐ODS worsened during fampridine compared with placebo (Bonferroni‐adjusted p = 0.007 for both), while other clinical outcomes showed no differences. Median nerve CMAP amplitude with proximal stimulation increased significantly during fampridine treatment (adjusted p = 0.040). No significant changes were observed in other electrophysiological variables, including nerve excitability testing. No serious adverse events occurred and adverse effects were predominantly mild.
Interpretation
Our study did not provide evidence that fampridine improves clinical function in CIDP patients with residual disability during stable immunoglobulin therapy. Targeting ion channel dysfunction in CIDP remains of interest, but alternative strategies may be required.
Keywords: chronic inflammatory demyelinating polyneuropathy, fampridine, nerve excitability testing, randomized controlled trial
1. Introduction
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is an autoimmune neuropathy characterized by slowly progressive weakness and sensory dysfunction in the arms and legs [1]. Despite advances in the understanding of the disease's pathophysiology, CIDP remains a challenging condition to manage, with significant variability in treatment response [2]. Hallmark features of CIDP, including gait impairment, weakness, and motor fatigue, can lead to substantial disability and impaired quality of life [1]. The pathogenesis of the disease is known to involve multifocal demyelination with remyelination and nerve fiber loss [3]. Electrophysiological characteristics include reduced nerve conduction velocity, abnormal temporal dispersion of the action potential, and motor conduction blocks [3, 4]. The myelinated fiber structure is known to consist of nodal and internodal regions separated by the juxtaparanode anchoring the sodium and potassium channels [5, 6]. The channels are responsible for generating action potential and nerve impulse conduction [5, 6]. CIDP is regarded as a primarily demyelinating disease; however, several studies have found axonal dysfunction [7, 8, 9]. Thus, nerve excitability testing (NET) using the threshold tracking technique has shown ion channel dysfunction involving both the sodium and potassium channels. Treatment with immunoglobulin, corticosteroids, and plasmapheresis is supposed to act via modulation of the autoimmune disease process in CIDP and thereby aims at halting demyelination and improving remyelination [10, 11]. There is currently no recommended treatment targeting axonal dysfunction in CIDP. A subset of patients with CIDP experience persistent disability and refractory symptoms despite conventional treatments, which underline the need for alternative therapeutic options to improve functioning [12].
Fampridine has been shown to improve impaired function in both the upper and lower extremities in multiple sclerosis (MS) [13, 14, 15]. Fampridine inhibits the fast voltage‐gated potassium channels and improves the conduction of action potentials in demyelinated nerve fibers [16, 17]. Fampridine has previously been tested in an open‐label study in CIDP [18]. Although the study found changes in clinical function, the changes were not statistically significant. Furthermore, the study was small and, in our opinion, inconclusive. We hypothesized that fampridine would also modulate ion channels in peripheral nerves and via this action lead to improved functioning in CIDP patients with refractory symptoms on conventional immune‐modulating therapies. The primary aim of this clinical trial was to investigate if fampridine can improve physical functioning and change electrophysiology in patients with CIDP with residual disability and persisting symptoms despite optimal treatment with immune modulation with immunoglobulins subcutaneously (SCIg) and intravenously (IVIg).
2. Methods
2.1. Ethical Approvals and Registration
The study is reported according to the CONSORT 2010 statement. The study was approved by the local Ethics Committee of Southern Denmark (S‐20200091) and the Danish Health Authorities (EUDRACT no.: 2020‐002438‐34), and it was registered in the EUDRACT database of clinical trials and the Danish Data Protection Authority. The study and its conduct were monitored by the GCP Units at Odense and Aarhus University Hospitals.
2.2. Trial Design
This study was designed as a two‐center, randomized, double‐blind, placebo‐controlled, crossover trial. An outline of the study is shown in Figure 1. After baseline observations, the patients were randomized to either treatment sequence, placebo‐fampridine or fampridine‐placebo. The double‐blind treatment periods were 4 weeks duration, and they were separated by a washout period of at least 2 weeks duration (see below). For each patient, the two treatment periods were initiated at the same time point relative to the most recent IVIg or SCIg administration, ensuring comparable timing within the individual immunoglobulin treatment cycle. Baseline observations were also obtained just before the second treatment period.
FIGURE 1.
Trial outline. v1, v2, v3, v4, v5, v6: Visit 1, 2, 3 during the first treatment period and visit 4, 5, and 6 during the second treatment period. The washout period varied depending on standard treatment, from 2 weeks for SCIg and either 4, 5, or 6 weeks for IVIg, depending on the treatment interval to match the duration from IVIg infusion to the baseline of the treatment period.
2.3. Participants
The study took place at the Department of Neurology, Odense University Hospital, and the Department of Neurology, Aarhus University Hospital. Patients with CIDP were recruited from January 2020 to September 2024 from the outpatient clinics of the departments.
The inclusion criteria were patients aged ≥ 18 and ≤ 80 years diagnosed with CIDP that fulfilled the 2010 European Federation of Neurological Societies/Peripheral Nerve Society criteria [19] and clinically stable during treatment with either SCIg or IVIg. At the time of inclusion, the patient's score on the Overall Neuropathy Limitations Scale (ONLS) had to be ≥ 1 for the lower extremities and/or ≥ 2 for the upper extremities. If the ONLS for the lower extremities was ≥ 1, the patient's six‐spot‐step test (SSST) had to be > 8.6 s. If the ONLS for the upper extremities was ≥ 2 for the upper extremities, the average nine‐hole‐pegboard test (9HPT) for both hands was > 23.0 s.
Patients diagnosed with other causes (vascular disease, spinal root affection, spinal stenosis, etc.) that affected the function of the lower extremities, significant systemic disease, or other diseases causing inability to walk were excluded. Patients with IgM‐MGUS were also excluded. Patients with a prior medical history of epilepsy, seizures, or impaired kidney function defined as eGFR < 80 mL/min, or pregnancy were also excluded from the study.
2.4. Interventions
The study medication was dosed twice a day. The medication was capsules with identical appearance, taste, and smell containing 10 mg fampridine or placebo. The placebo capsules were manufactured and packed at Glostrup Apotek (Hovedvejen 101, 2600 Glostrup, Denmark), and the fampridine capsules were N07XX07 FAMPYRA (Lotnr. 30833011, Biogen). Adherence to the treatment was monitored at the end of each treatment period.
Each treatment period included three visits. Between the two treatment periods, the patients underwent a washout period that varied depending on immunoglobulin treatment. For patients treated with SCIg, the washout period was 2 weeks. For patients treated with IVIg, the washout period was either 4, 5, or 6 weeks corresponding to the individual IVIg treatment interval. This ensured that, for each patient, the two treatment periods were initiated at the same time point relative to the most recent immunoglobulin administration and at a comparable point within the individual immunoglobulin treatment cycle.
All visits included clinical testing with Grip strength (JAMAR, Lafayette Instrument Inc., Lafayette, IN, USA), Nine‐hole‐peg test (9‐HPT) [20], timed‐10‐m‐walk test (10‐MWT), six‐spot‐step test (SSST) [21], MRC sum score [22], and INCAT sensory sum score [23] and questionnaires measuring everyday function with ONLS [24], Rasch‐built Overall Disability Scale (R‐ODS) [25], and Neuropathic Pain Symptom Inventory [26]. During visit 2, visit 3, visit 5, and visit 6, overall change was scored using Patient Global Impression of Change (PGIC) with verbal scores (much improved, moderately improved, slightly improved, no change, slightly worse, moderately worse, much worse) converted to numerical scores +3 to −3. During each treatment period's first visit (visit 1 and visit 4) and last visit (visit 3 and visit 6), participants were examined using nerve conduction study and NET.
Adverse events were monitored throughout the study. If necessary, additional phone calls or visits were arranged. Patients were contacted 4 weeks after the ‘end of study’ to determine whether adverse events had been resolved and whether long‐term late adverse events had appeared. Adverse events were systematically recorded on each visit by blinded investigators. Additional visits were arranged when needed.
2.5. Primary Outcome
The primary outcome was the average change in SSST and 9‐HPT during treatment with fampridine and placebo. SSST and 9‐HPT were measured at baselines (visit 1/4) and during visits 2/5 and visits 3/6.
SSST and 9‐HPT were selected as co‐primary outcomes to assess functional performance of the lower and upper extremities, respectively. Previous work in patients with chronic inflammatory polyneuropathy demonstrated greater responsiveness of the SSST to treatment‐related change than conventional timed walking, including greater effect size, standardized response mean, and relative efficiency compared with the timed 25‐ft walk [21]. The 9‐HPT was selected as the corresponding upper‐extremity functional measure, as the SSST uses a conceptually parallel test paradigm combining speed with coordination and sensorimotor function.
2.6. Secondary Outcome
Secondary clinical outcomes were the change in Grip strength, 10‐MWT, MRC score, and INCAT sensory sum score. Questionnaire‐based outcomes were ONLS, R‐ODS, and PGIC. All were measured at baselines (visit 1/4) and during visits 2/5 and 3/6.
Secondary electrophysiological outcomes were nerve excitability variables of the NET and conduction velocity, amplitude, and f‐wave of the median and peroneal nerves measured by nerve conduction studies performed at baseline and at the end of each study period.
2.7. Sample Size
The primary objective was to test the differences from baseline to the end of fampridine treatment with respect to the change in time to perform the SSST and 9‐HPT. For the SSST, if the minimally relevant difference in time reduction between treatments is set at 2.0 s and the standard deviation in time reduction from baseline to treatment set to 3.5 s (conservative estimate) [21], a total of 33 patients were needed (α = 0.05, β = 0.90, one‐sample comparison). For the 9‐HPT, if the minimally relevant difference in time reduction between treatments is set at 2.5 s and the standard deviation in time reduction from baseline to treatment set to 4.1 s (conservative estimate) [27], a total of 31 patients were needed (α = 0.05, β = 0.90, one‐sample comparison).
2.8. Randomization
Participants who met the study criteria and consented to participate after receiving verbal and written information were assigned a participation number. If the study criteria were met at baseline, participants were assigned a randomization number that determined the order of treatment with fampridine and placebo. Treatment sequences were assigned randomly by a computer‐generated randomization list. Participants were allocated to the next available randomization number at the pertinent site. Investigators and participants were blinded to the randomization list and remained blinded until the study's completion. The treatment sequence for each participant was kept in a sealed envelope at the respective study sites for emergencies, and the Hospital pharmacy, Sygehus Apotek Fyn, had a complete randomization list.
2.9. Statistical Methods
Unadjusted statistical analysis of the co‐primary outcomes (average of 9‐HPT and SSST as measured in time) was performed by a general linear model (XT‐mixed in STATA) for repeated measurements with treatment as a factor, baseline value of outcome measures as covariates, treatment period as a fixed effect, and patients as a random effect. Exploratory statistical analysis was performed with time ‘from onset of symptom to treatment’ as a co‐variant.
The primary analyses were performed according to the intention‐to‐treat principle, with all randomized participants contributing available data in the mixed‐effects models. For missing end‐of‐period observations, the last available on‐treatment observation within the same treatment period was carried forward. Data were not imputed across treatment periods. Participants with incomplete treatment periods therefore contributed the available observations to the mixed‐effects analyses. Per‐protocol analyses included participants who completed both treatment periods.
To assess potential period, sequence, and carryover effects related to the crossover design, additional sensitivity analyses were performed. Treatment period and randomized treatment sequence were included as fixed effects. Potential carryover was explored by assessing whether the change between the pre‐treatment baselines of the first and second treatment periods differed according to randomized treatment sequence, using a period‐by‐sequence interaction.
The same procedure was used for all secondary outcomes (electrophysiological data from NET (variables of ion channel function) and nerve conduction studies, and clinical tests of grip strength, 10‐MWT, MRC score, INCAT sensory sum score, ONLS, R‐ODS, and PGIC).
An exploratory sensitivity analysis excluding patients with MGUS was performed to assess whether the presence of a monoclonal gammopathy materially influenced the clinical treatment comparisons.
Statistical significance was assessed at the 5% level. For the seven secondary clinical outcomes, p values were adjusted for multiple testing using the Bonferroni method. For nerve conduction studies, Bonferroni correction was applied within the five predefined nerve conduction variables. Both unadjusted and Bonferroni‐adjusted p values are reported in the tables, and statistical significance of secondary outcomes was based on the adjusted p values. For NET outcomes, Bonferroni correction was applied across the 29 predefined nerve excitability variables.
3. Results
3.1. Screening, Inclusion, and Randomization
A total of 81 patients were screened for eligibility, and 29 fulfilled the inclusion criteria. Of these, 28 were randomized. One patient was found ineligible after the SSST and 9‐HPT were performed too quickly on the day of randomization (Figure 2).
FIGURE 2.
Patient flow in the trial. IVIg, intravenous immunoglobulin; SCIg, subcutaneous immunoglobulin.
All 28 randomized patients were included in the intention‐to‐treat analysis. However, four patients withdrew from the study due to side effects, leaving 24 patients who completed the study per protocol (PP). Of the dropouts, four patients completed one full treatment cycle of 4 weeks. Three of these four patients completed 2 weeks of the alternate treatment period before withdrawal, while one patient discontinued after only 2 days of the second treatment period.
All 28 patients participated in clinical testing. Three patients declined to undergo nerve conduction studies, and NET data could not be obtained in one patient due to poor‐quality electrophysiological responses.
3.2. Patient Characteristics
Patient characteristics are given in Table 1. The patients included ranged in age from 63 to 74 years. At the time of inclusion, 18 patients were treated with SCIg and 10 patients with IVIg. The median time in months from the onset of symptoms to diagnosis was 28.5, and the median time from diagnosis to inclusion in the study was 69.9 months. Of the included patients, seven participants had a diagnosis of M‐component of uncertain significance at the time of inclusion. Further characteristics, including neuropathy scores and neurophysiological variables, are presented in Table 1.
TABLE 1.
Baseline characteristics.
| Patients (n = 28) | |
|---|---|
| Clinical characteristics | |
| Age (median, range) | 70 (63–74) |
| Sex (M/F) | 21/7 |
| Alcohol consumption over 5 units per day (n) | 0 |
| Diabetes (n) | 3 |
| Medical treatment other than immunoglobulin | 22 |
| Onset of symptoms to diagnosis (months) (median, range) | 28.5 (6–62) |
| Diagnosis to inclusion (months) (median, range) | 69.9 (43.5–97.2) |
| Fulfill the criteria for demyelination polyneuropathy (n) | 23 a |
| Cerebrospinal fluid protein level at diagnosis (median, range) | 0.61 (0.40–1.00) |
| Non‐IgM MGUS (n) | 7 |
| Immunoglobulin at inclusion (g/kg/week) (median, range) | 0.33 (0.27–0.39) |
| Clinical functional scores at inclusion | |
| SSST (median, range) | 10.6 (8.2–16.2) |
| Nine‐hole‐peg‐test (s) (median, range) | 31.0 (25.3–41‐5) |
| ODSS (arms) (median, range) | 2 (2–2) |
| ODSS (legs) (median, range) | 2 (1–3) |
| ODSS (total) (median, range) | 4 (3–5) |
| Median nerve at inclusion shown as standard deviation from normalized reference material | |
| Distal motor latency (ms) (median, range) | 4.23 (3.40–5.91) |
| Conduction velocity (m/s) (median, range) | 41.5 (35.3–48.9) |
| Compound muscle action potential, distal (mV) (median, range) | 6.5 (4.9–9.3) |
| Compound muscle action potential, proximal (mV) (median, range) | 4.4 (3.5–8.1) |
| f‐wave (ms) (median, range) | 39.0 (34.4–41.3) |
| Peroneal nerve at inclusion shown as standard deviation from normalized reference material | |
| Distal motor latency (ms) (median, range) | 4.99 (3.94–5.79) |
| Conduction velocity, distal (m/s) (median, range) | 33.9 (28.3–42.9) |
| Compound muscle action potential, distal (mV) (median, range) | 1.87 (1.28–4.30) |
| Compound muscle action potential, proximal (mV) (median, range) | 1.48 (1.02–2.80) |
| f‐wave (ms) (median, range) | 65.9 (53.8–74.7) |
Note: Other medical treatments included treatment for hypertension, anticoagulants, antithrombotics, pain treatment including neuropathic pain treatment, diabetic treatment, and anti‐cholesterol treatment.
One patient had Lewis‐sumner syndrome. Two patients had pure sensory CIDP. For two patients, diagnostic data were not obtainable, however, patient journals, including descriptive nerve conduction study evaluations, confirmed the diagnosis.
3.3. Sensitivity Analyses
In sensitivity analyses at the end of each treatment period, a period effect was observed for SSST (p = 0.042), whereas no sequence effect was detected (p = 0.110). No significant period or sequence effects were observed for 9‐HPT (p = 0.352 and p = 0.798, respectively). There was no significant period‐by‐sequence interaction between the pre‐treatment baselines for either SSST (p = 0.234) or 9‐HPT (p = 0.870), providing no evidence of detectable carryover.
3.4. Primary Outcomes
SSST and 9‐HPT during treatment with fampridine and placebo are shown in Figure 3. During treatment with fampridine, SSST changed from 12.28 s (SD 5.66) to 12.07 s (SD 5.45), and with placebo, from 12.80 s (SD 5.91) to 12.00 s (SD 6.12), with a mean difference in change of 0.6 s (SD 2.1). For the 9‐HPT, a change from 40.96 s (SD 33.93) to 40.25 s (SD 33.45) was observed during fampridine treatment, and from 37.44 s (SD 22.99) to 34.91 s (SD 17.41) during placebo, with a mean difference in change of 0.4 s (SD 11.8). There were no significant differences observed between the changes during treatment with fampridine and placebo for either SSST (p = 0.154) or 9‐HPT (p = 0.857) (Table 2).
FIGURE 3.
Co‐primary outcomes. Time to perform the six‐spot‐step‐test (SSST) (A) and the nine‐hole peg test (9‐HPT) (B) during the trial for patient randomized to the fampridine/placebo sequence (blue line) or the placebo/fampridine sequence (red line). Data are shown as mean values with a 95% confidence Visits: 1 = baseline, 2 = day 14, 3 = end‐of‐treatment, 4 = baseline, 5 = day 14, 6 = end‐of‐treatment.
TABLE 2.
Clinical results.
| Fampridine | Placebo | Comparison | |||||
|---|---|---|---|---|---|---|---|
| Baseline | End‐of‐treatment | Baseline | End‐of‐treatment | Mean difference (SD) | Unadjusted p value | Adjusted p value | |
| Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | ||||
| All patients (n = 28) | |||||||
| Six‐Spot‐Step‐Test (SSST) | 12.28 (5.66) | 12.07 (5.45) | 12.80 (6.79) | 12.00 (6.12) | 0.6 (2.1) | 0.154 | — |
| Nine‐hole peg test (9‐HPT) | 40.94 (33.93) | 40.25 (5.45) | 35.35 (16.28) | 34.91 (17.41) | 0.4 (11.8) | 0.857 | — |
| Grip strength | 30.04 (11.34) | 29.24 (10.78) | 28.58 (10.49) | 29.77 (10.80) | −2.0 (3.3) | 0.001 | 0.007 |
| Medical Research Council sum score (MRC) | 87.0 (3.6) | 87.4 (2.7) | 86.9 (3.0) | 87.0 (3.1) | 0.3 (2.2) | 0.492 | 1.000 |
| 10‐m walk test | 9.84 (4.20) | 9.59 (3.91) | 10.46 (6.26) | 10.14 (6.58) | 0.1 (2.2) | 0.86 | 1.000 |
| Neuropathic Pain Symptom Inventory (NPSI) | 15.1 (17.4) | 16.2 (17.9) | 15.1 (16.6) | 15.9 (17.0) | 0.5 (12.9) | 0.834 | 1.000 |
| Rasch‐built Overall Disability Scale (R‐ODS) | 34.2 (7.7) | 33.1 (7.7) | 32.8 (7.5) | 34.0 (7.8) | −2.5 (4.1) | 0.001 | 0.007 |
| Overall Neuropathy Limitations Scale (ONLS) | 3.9 (1.1) | 4.0 (1.2) | 3.8 (1.5) | 3.6 (1.3) | 0.2 (1.5) | 0.591 | 1.000 |
| Patient Global Impression of Change (PGIC) | — | −0.2 (0.9) | — | 0.2 (1.1) | −0.4 (1.3) | 0.081 | 0.567 |
| Non‐MGUS patients (n = 21) | |||||||
| Six‐Spot‐Step‐Test (SSST) | 12.80 (6.28) | 12.24 (6.07) | 13.35 (7.58) | 12.36 (6.84) | 0.4 (2.6) | 0.473 | — |
| Nine‐hole peg test (9‐HPT) | 42.15 (38.17) | 41.31 (37.07) | 33.53 (12.12) | 33.04 (12.47) | 0.3 (15.2) | 0.916 | — |
| Grip strength | 30.16 (12.80) | 29.63 (12.03) | 28.71 (11.42) | 30.07 (12.00) | −1.9 (4.2) | 0.015 | 0.105 |
| Medical Research Council sum score (MRC) | 87.1 (3.9) | 87.5 (2.8) | 86.9 (3.2) | 87.2 (3.2) | 0.1 (2.7) | 0.856 | 1.000 |
| 10‐m walk test | 10.04 (4.65) | 9.70 (4.27) | 10.81 (7.02) | 10.59 (7.41) | −0.1 (2.9) | 0.807 | 1.000 |
| Neuropathic Pain Symptom Inventory (NPSI) | 15.8 (18.8) | 15.6 (18.0) | 16.0 (17.9) | 14.8 (16.5) | 0.5 (12.9) | 0.834 | 1.000 |
| Rasch‐built Overall Disability Scale (R‐ODS) | 34.2 (7.7) | 33.1 (7.7) | 32.8 (7.5) | 34.0 (7.8) | −2.4 (4.6) | 0.006 | 0.042 |
| Overall Neuropathy Limitations Scale (ONLS) | 4.0 (1.1) | 4.0 (1.1) | 3.9 (1.5) | 3.8 (1.3) | 0.2 (1.5) | 0.593 | 1.000 |
| Patient Global Impression of Change (PGIC) | — | −0.1 (0.7) | — | 0.1 (1.2) | −0.2 (1.5) | 0.529 | 1.000 |
Note: Data are shown each clinical examined parameter for all patients and non‐MGUS patients. Mean values are shown for each visit during fampridine and placebo treatment. Comparison is shown as a difference in mean value from baseline to end‐of‐treatment between treatment with fampridine and treatment with placebo. Comparison is presented as the difference in change from baseline to end of treatment between fampridine and placebo. For secondary clinical outcomes, both unadjusted and Bonferroni‐adjusted p values are reported. Bonferroni adjustment was performed across the seven secondary clinical outcomes. Adjusted p values < 0.05 were considered statistically significant. Co‐primary outcomes were not included in this multiplicity adjustment.
3.5. Secondary Clinical Outcomes
The secondary clinical scores during treatment are detailed in Table 2.
GS and R‐ODS score changes indicated worsening on fampridine with GS decreasing from 30.04 kg (SD 11.34) to 29.24 kg (SD 10.78) on fampridine and increasing from 28.48 kg (SD 10.49) to 29.77 kg (SD 10.80) on placebo, and R‐ODS decreasing from 34.2 (SD 7.7) to 33.1 (SD 7.7) on fampridine and increasing from 32.8 (SD 7.5) to 34.0 (SD 7.8) on placebo. Both changes remained statistically significant after Bonferroni correction (adjusted p = 0.007 for GS and adjusted p = 0.007 for R‐ODS) (Table 2). PGIC showed a numerical difference between fampridine and placebo (unadjusted p = 0.081; adjusted p = 0.567). The reported change for fampridine was −0.2 (SD 0.9) compared to placebo, with a reported change of 0.2 (SD 1.1). Correlation analysis revealed no significant association between GS and R‐ODS (ρ = 0.045, p = 0.65).
No significant difference between changes during treatment with fampridine and placebo was found for MRC, 10‐MWT, NPSI, or ONLS (Table 2).
For exploratory analysis, patients with MGUS were excluded. Clinical scores are detailed in Table 2.
The primary outcomes showed results similar to the main analysis for all patients. For SSST, during fampridine, the score changed from 12.80 s (SD 6.28) to 12.24 s (SD 6.07), compared to placebo with a change from 13.35 s (SD 7.58) to 12.36 s (SD 6.84). For 9‐HPT, changes were 42.15 s (SD 38.17) to 39.64 s (SD 23.97) during fampridine and 33.53 s (SD 12.12) to 33.04 s (SD 12.47) during placebo. The mean difference analysis comparing changes during fampridine and placebo for SSST and 9‐HPT also showed no significant difference (Table 2).
In the exploratory analysis, excluding patients with MGUS, nominal differences were observed for GS (unadjusted p = 0.015) and R‐ODS (unadjusted p = 0.006). After Bonferroni correction, the difference remained statistically significant for R‐ODS (adjusted p = 0.042), but not for GS (adjusted p = 0.105) (Table 2).
No other variable showed a significant difference in mean change during fampridine and placebo (Table 2).
3.6. Secondary Electrophysiological Outcomes
Standard nerve conduction studies (Table S1) showed that the median nerve CMAP amplitude increased at both distal (p = 0.044) and proximal (p = 0.008) stimulation during fampridine treatment in unadjusted analyses. After Bonferroni correction, the increase remained statistically significant only at proximal stimulation (adjusted p = 0.040), whereas the distal finding was no longer significant (adjusted p = 0.220). No other nerve conduction variables showed statistically significant differences after correction for multiple testing. No significant changes were observed during stimulation of the peroneal nerves.
The results of NET are shown at the end of the study, comparing fampridine to placebo (Figure 4).
FIGURE 4.
Summary of nerve excitability testing. Current‐threshold relationship (A), strength‐duration properties (B), threshold electrotonus (C), and recovery cycle (D) in patients with chronic inflammatory demyelinating polyneuropathy during treatment with fampridine (red) and placebo (black). Data are shown for ‘End of treatment’ mean values for all patients. 1: The increase in the hyperpolarizing I/V slope suggests reduced effective potassium conductance during membrane hyperpolarization. 2: Current‐threshold (I/V) relationship plotted with response to hyperpolarizing current, showing a positive change in threshold analog of input conduction. 3: The modest reduction in TEd20 peak implies a reduced requirement for persistent sodium channel activation during sustained depolarization. 4: The reduction in superexcitability at 5 ms indicates stabilization of post‐spike membrane behavior, consistent with decreased pathological internodal potassium currents typically observed in demyelinated axons.
No variables showed a statistically significant difference in change from baseline to end‐of‐study comparing fampridine to placebo. However, non‐significant differences were observed in four variables comparing fampridine treatment to placebo: hyperpolarizing IV‐slope 0.75 (SD 2.1) (p = 0.058), stimulus–response slope 1.27 (SD 3.6) (p = 0.064), superexcitability at 5 ms 5.53 (SD 17.6) (p = 0.096), and TEd20 peak −3.86 (SD 10.7) (p = 0.057) (Table S2).
3.7. Expectation of Drug Effect
Correlation analysis between expectation of drug effect and patient global impression of change revealed no significant association (ρ = −0.055, p = 0.784).
3.8. Exploratory Analysis
A clinically significant change threshold defined by a 20% reduction in performance from baseline was 2.51 s (SD 1.24) for SSST and 7.63 s (SD 5.33) for 9‐HPT (Figure 5). One patient showed significant clinical improvement performing SSST during fampridine treatment, while two patients showed significant improvement during placebo. Two different patients showed significant clinical improvement performing 9‐HPT during fampridine treatment, with no patients improving during placebo. However, only one of the three patients reported a mild effect on PGIC, whereas one patient reported no change, and the last patient reported a mild negative effect. The number‐needed‐to‐treat for fampridine was 14, measured by both 9‐HPT and SSST. This NNT is, of course, not statistically significant. The percentage change from baseline to end‐of‐treatment during fampridine treatment was 0.61% (SD 13.91) and 1.03% (SD 11.09).
FIGURE 5.
Change in co‐primary outcomes. Individual improvement (+) or decline (−) for each patient comparing the difference of fampridine from baseline to end‐of‐treatment to placebo from baseline to end‐of‐treatment during the six‐spot‐step test (A) and the 9‐hole‐peg test (B). Data are shown as a mean difference in percentage. The dotted lines for each plot indicate the minimal clinically significant improvement of 20%.
3.9. Adverse Events and Side Effects
No serious adverse events were observed during the study. However, 18 patients reported side effects during the treatment periods. All but one patient experienced side effects only during fampridine treatment; one patient reported side effects during both placebo and fampridine treatment. All reported side effects were listed in the Summary of Product Characteristics. Overall, adverse events were infrequent and predominantly mild.
The most commonly reported symptoms were paresthesia (reported by 27.0% with mild symptoms in 16.2% and moderate in 10.8%), tremor (21.6% with mild symptoms in 10.8% and moderate in 10.8%), gait instability (21.6% with mild symptoms in 10.8% and moderate in 10.8%), headache (16.2%, all with mild symptoms), and insomnia (16.2%, all with mild symptoms). Nausea was reported mildly by 5.4%, while dyspepsia occurred mildly in 18.9%. Other adverse effects, including dyspnea, fatigue, vertigo, anxiety, flu‐like symptoms, and urinary discomfort, were rare (< 10%), all with mild symptoms. No cases of constipation, vomiting, or serious infections were reported.
4. Discussion
Overall, our study provided no evidence of clinically meaningful improvement in function, as measured by SSST and 9‐HPT, during fampridine treatment compared with placebo in this cohort of patients with CIDP. Fampridine treatment caused a minimal decrease of 0.21 s to perform the SSST and a minimal decrease of 0.80 s to perform the 9‐HPT, and these changes were not statistically different from the changes seen within the placebo treatment. The co‐primary outcomes did not differ significantly between fampridine and placebo. Among the secondary clinical outcomes, GS and R‐ODS showed worsening during fampridine treatment compared with placebo and remained statistically significant after Bonferroni correction, whereas no significant differences were observed for the remaining secondary clinical outcomes. In the nerve conduction studies, only the increase in proximal median nerve CMAP amplitude remained statistically significant after Bonferroni correction. No statistically significant effects were found on other electrophysiological variables. Notably, a similar increase was not found in amplitudes of the peroneal nerves; however, the sample size was fairly small for peroneal nerve analysis.
The change in time to perform the SSST (0.6%) and 9‐HPT (1.0%) seen during treatment with fampridine was not clinically relevant [28, 29]. Previous studies of fampridine in the treatment of patients with multiple sclerosis (MS) have found an improvement of 23% and 24.7% in walking speed during the Timed 25‐Foot Walk [14, 15, 30], and other studies have stated that a minimally clinically significant change in this patient group is a 20% decrease in time in the Timed 25‐Foot Walk [28, 29] and 9‐HPT [28]. In CIDP patients, a study has compared meaningful clinical changes by performing Timed 25‐Foot Walk and SSST during IVIg treatment and found an improvement of 8.3% (0.6 s) during Timed 25‐Foot Walk and 16.3% (2.3 s) in SSST after IVIg treatment to be clinically meaningful [21]. Similarly, another study showed statistically significant improvements upon IVIg treatment in SSST with 11.3% (1.16 s) and 9‐HPT 7.7% (2.36 s) [9]. In CIDP patients, it has been proposed that the most sensitive parameter for detecting clinically relevant changes is GS [9, 31]. In our study, patients treated with fampridine experienced a mild decline in GS of 0.8 kg. Although the within‐treatment changes were small, the difference in change between fampridine and placebo for GS remained statistically significant after correction for multiple testing (adjusted p = 0.007). A similar worsening was observed for R‐ODS (adjusted p = 0.007). The study did not reach the prespecified sample size of 31–33 participants and was therefore underpowered relative to the original power calculation. Although the observed differences in the co‐primary outcomes were small and did not suggest a clinically meaningful benefit in this cohort, the limited sample size reduces the precision of the effect estimates and prevents us from excluding a smaller treatment effect.
Fampridine has previously been tested in patients with CIDP in a small open‐label study by Leussink et al., where 10 patients were treated for 28 days [18]. The results of the study showed that fampridine treatment led to a decrease in the 25‐ft walk of 1.2 s (11%) and 3.4 s (15%) performing 9‐HPT. Although these findings seem to show improvement levels that are clinically meaningful by comparison with other studies [9, 21], the outcomes were not statistically significant, and there was no control treatment or condition. The study of Leussink et al. had the most comparable set‐up to our clinical trial; however, our study did not provide evidence supporting a clinical benefit of fampridine in our CIDP cohort.
The study by Leussink et al. [18] found a small decrease in nerve conduction velocity of −2.7 ms, and a slight increase in compound muscle action potential of 0.24 mV, though changes were not statistically significant. Similarly, we did not find any statistically significant changes in nerve conduction velocity. In the unadjusted analyses, median nerve CMAP amplitude increased at both proximal and distal stimulation; however, only the proximal increase remained statistically significant after Bonferroni correction. The increase in proximal median nerve CMAP amplitude that remained significant after correction for multiple testing is of potential biological interest, but its significance remains uncertain. Although there could be a difference in types of potassium channels in the peripheral and central nervous system, fampridine has previously been shown to be effective in studies of isolated nerves in vitro [32] and rodent models [33] by blocking potassium channels. The blockage of potassium channels could overcome conduction blocks, broaden the action potential, and cause hyperexcitability with sporadic firing and multiple spikes discharging after a single stimulus. In an experimental model of autoimmune neuritis, fampridine has been shown to cause an increased motor conduction velocity and amplitude in rodents treated with fampridine when compared to controls [33]. The increase in median nerve CMAP amplitude during fampridine treatment is of potential biological interest, but its significance remains uncertain. The finding was not reproduced in the peroneal nerves and was not accompanied by improvement in clinical outcomes or significant changes in NET variables. It should therefore be regarded as exploratory and requires confirmation in larger studies.
To our knowledge, no previous study has investigated nerve excitability changes during fampridine treatment in patients with CIDP. Previous excitability studies in CIDP have demonstrated abnormalities in sodium and potassium channel‐related measures and changes following IVIg treatment [7, 8, 9]. In the present study, however, no NET variable showed a statistically significant difference between fampridine and placebo. Numerical differences were observed in hyperpolarizing I/V slope, TEd20 peak, stimulus–response slope, and superexcitability at 5 ms, but these findings were not accompanied by consistent changes in related NET variables. They should therefore be interpreted cautiously and regarded as exploratory and hypothesis‐generating rather than as evidence of a specific effect of fampridine on peripheral axonal ion channel function. The fampridine and placebo treatment periods were synchronized within each participant relative to immunoglobulin administration, thereby minimizing systematic differences in immunoglobulin timing between treatment periods. Nevertheless, ongoing immunoglobulin treatment may have influenced the absolute NET measurements and potentially reduced the ability to detect small fampridine‐specific effects. Further studies with larger sample sizes and prespecified electrophysiological hypotheses would be required to determine whether these observations represent reproducible pharmacological effects. Although the increase in median nerve CMAP amplitude suggests a possible electrophysiological effect, the absence of corresponding changes in peroneal nerve CMAP, NET variables, or clinical outcomes limits the strength of any mechanistic interpretation.
Our study was performed with the standard dosage of 10 mg twice daily, used for patients with MS [13, 34]. In studies of the effect of fampridine in isolated peripheral nerves [17, 35, 36], fampridine improves nerve conduction by increasing the duration of the action potential and improving conduction. This effect, however, shows dependence on the concentration of fampridine and nerve fiber structure. The dosage‐dependent effect has also been shown in guinea pig models of spinal cord contusion [37, 38, 39]. Shi et al. [39] showed that acute and chronic spinal cord injuries required different dosages of fampridine to improve nerve conduction, while Jensen et al. [37] reported an increase of action potential amplitude of 100% at a fampridine concentration of 100 μM compared to only 43% at 1 μM. One could speculate that the lack of clinical effect of fampridine in our study cohort could be explained by insufficient potassium channel blockage in the peripheral nervous system, though we applied the maximal recommended dosage of fampridine. It has previously been highlighted by Smith et al. [40] that the maximal recommended serum dosage in humans of 1 μM [41] is 1000–5000 times lower than the drug concentration used in experimental studies in isolated nerves and spinal roots [35]. An increase in fampridine dosage for patients is, however, not recommended as high doses can lead to inhibition of cardiac potassium channels with the risk of prolongation of the QT interval and arrhythmias [42]. A possible solution to this limitation could be the development of a drug or drug delivery system specifically targeting potassium channels in the peripheral nervous system, thus circumventing the cardiac risk.
Another potassium channel blocking agent, similar to fampridine, 3,4‐aminopyridine, has been tested in several peripheral nervous system disorders. The drug demonstrated a positive effect on muscle strength and autonomic symptoms in patients with Lambert‐Eaton myasthenic syndrome [43]. In a randomized placebo‐controlled, crossover study, 3,4‐aminopyridine was tested in 27 hereditary neuropathies and seven acquired demyelinating polyneuropathies [44], finding no significant differences when comparing 3,4‐aminopyridine to placebo in neurologic disability score, isometric muscle strength testing, compound muscle potential amplitudes, or nerve conduction. In a smaller study, 3,4‐aminopyridine was tested in two CIDP patients and four patients with Guillain‐Barré syndrome [45], concluding that 3,4‐aminopyridine did not cause any clinical or electrophysiological changes. Although 3,4‐aminopyridine has only been tested in these small cohorts of patients, these small studies have not demonstrated a clinical benefit of 3,4‐aminopyridine in patients with CIDP.
The severe axonal damage seen in our patient cohort, particularly in the lower extremities, was present already at baseline and is likely attributed to the long‐term effects of CIDP on the nerves. The extent of axonal damage may be a contributing factor to the lack of response to fampridine treatment. This has been shown in patients with MS, where severe axonal loss and degeneration are predictors of insufficient response to fampridine treatment [46, 47, 48]. Although current guidelines for fampridine treatment are based solely on clinical testing [49], it has been suggested that central motor conduction time could be a predictor for the effect of fampridine treatment and should be incorporated as a parameter factor in the recommendations [50].
4.1. Strengths and Limitations
Our study has several limitations, most notably that the prespecified sample size was not reached. Based on the co‐primary outcomes, 31–33 participants were required, whereas 28 patients were randomized, and 24 completed both treatment periods per protocol. Consequently, the study had lower statistical power and less precise effect estimates than originally planned. The observed differences in SSST and 9‐HPT between fampridine and placebo were small and did not provide evidence of a clinically meaningful benefit in this cohort. However, the limited sample size means that a smaller treatment effect cannot be definitively excluded. Another potential limitation of the crossover design is the possibility of period, sequence, or carryover effects. In the present study, fampridine and placebo treatment periods were synchronized within each participant relative to immunoglobulin administration, reducing the risk that differences in IVIg or SCIg timing influenced treatment comparisons. Sensitivity analyses showed no evidence of a sequence effect for either co‐primary outcome at the end‐of‐period assessment and no evidence of a detectable carryover effect based on the pre‐treatment baselines. A period effect was observed for SSST, but not for 9‐HPT. As immunoglobulin timing was matched within participants across treatment periods, this finding is unlikely to reflect systematic differences in the immunoglobulin treatment cycle and may instead represent temporal variability or chance. Treatment duration should also be considered when interpreting the negative clinical findings. Although changes in ion channel function may occur within minutes of exposure in vitro [35], and clinical effects of fampridine in patients with MS have been reported within 14–28 days [15], it cannot be excluded that a treatment period longer than 28 days may be required for electrophysiological effects to translate into clinically meaningful improvements in physical function.
A major strength of our study was the randomized, placebo‐controlled, and double‐blind design with Good Clinical Practice monitoring. The study was performed as a two‐center trial, and though the patient sample was relatively small, this increased the patient representation. Additionally, the diagnosis of each included patient was validated according to the 2010 European Federation of Neurological Societies/Peripheral Nerve Society criteria to secure correct reporting [19]. Another strength of the study was the extensive clinical and neurophysiological testing used to assess the effects of fampridine treatment, providing a detailed and in‐depth evaluation of treatment responses.
4.2. Perspective
Despite the availability of immune modulatory therapies such as IVIg and SCIG, a significant proportion of patients with CIDP still suffer from debilitating residual symptoms. This highlights the need for development of new drugs or treatment strategies to relieve symptoms, improving physical function, and QOL in this patient group. While our study provided no evidence that potassium channel blockade with fampridine meaningfully improved upper‐ or lower‐extremity function in this CIDP cohort, ion channel dysfunction remains a pathophysiologically relevant area for future investigation. Based on the present findings, fampridine cannot currently be recommended as symptomatic treatment for residual disability in CIDP outside a research setting.
As our patient cohort consisted of patients suffering from CIDP for a median of 70 months, perhaps prospective testing of fampridine should focus on newly diagnosed patients with less nerve damage.
5. Conclusion
In this cohort of patients with CIDP and residual disability despite stable immunoglobulin treatment, fampridine did not provide evidence of a clinically meaningful improvement in physical function compared with placebo. An increase in proximal median nerve CMAP amplitude was observed after correction for multiple testing, but this finding was not accompanied by clinical benefit or consistent changes in other electrophysiological measures. Given the limited sample size, smaller treatment effects or effects in other CIDP populations cannot be excluded. Further studies may explore whether selected patient subgroups, including patients with less advanced axonal damage, could respond differently to potassium channel modulation. Symptomatic treatment of residual loss of clinical function remains important, and we propose further research in the field.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1: Nerve conduction studies.
Table S2: Nerve excitability study.
Acknowledgments
The study was supported by the Novo Nordisk Foundation, grant no. NNF 18OC0053006.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Nerve conduction studies.
Table S2: Nerve excitability study.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.