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Distribution-based estimates of minimum clinically important difference in cognition, arm function and lower body function after slow release-fampridine treatment of patients with multiple sclerosis
Multiple Sclerosis and Related Disorders, Volume 7, May 2016, Pages 58–60
To provide distribution-based estimates of the minimal clinical important difference (MCID) after slow release fampridine treatment on cognition and functional capacity in people with MS (PwMS).
MCID values were determined after SR-Fampridine treatment in 105 PwMS. Testing included the Timed 25 Foot Walk (T25FW), the Symbol Digit Modalities Test (SDMT), the Six Spot Step Test (SSST), the 9-Hole-Peg-Test (9-HPT), and the 5-Time-Sit-To-Stand test (5-STS).
MCID values: T25FW 17.8% (9.1–17.8), SDMT 17.1% (9.2–17.1), SSST 16.7% (8.5–16.7), 9-HPT 15.3% (0–15.3), and 5-STS 34.6% (16.9–34.6).
This study presents distribution-based estimates of MCID values for the SSST, the 9-HPT, and the 5-STS and confirms MCID estimates for the T25FW and the SDMT.
Keywords: Multiple sclerosis, MCID, Minimal clinically important difference, Change, Rehabilitation, Axonal loss, Demyelination.
Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system that predominantly affects young and middle-aged adults. The disease mechanism is characterized by demyelination and a subsequent axonal conduction block that severely debilitates transmission of the action potential (Judge and Bever, 2006). 4-aminopyridine (AP) is a potent blocker of voltage gated potassium channels. It has shown ability to reestablish axonal nerve conduction improving neurological functions in people with MS (PwMS) (Hayes, 2007). Fampridine (SR-Fampridine) now provides a slow-release formulation of AP. Studies have shown beneficial effect of SR-Fampridine on walking speed measured by the T25FW and muscle strength in the lower extremities measured by The Lower Extremity Manual Muscle Test (LEMMT) (Goodman et al., 2010), whereas other domains have been sparsely investigated. Recent results from our group suggest an effect on cognition, balance and coordination PwMS measured by the SDMT and the SSST (Jensen et al., 2014).
The effects of a given intervention may be demonstrated by a statistically significant change in the outcomes. However, statistical significance does not imply that the change is beneficial to the individual in daily life. The smallest change that is clinically meaningful and can be felt by the patient is termed the Minimal Clinical Important Difference (MCID). When treated with SR-Fampridine Hobart et al. estimated the MCID of the T25FW to be >20%, though improvement of >15% indicated small or moderate benefit when compared with changes on the 12-Item Multiple Sclerosis Walking Scale (MSWS-12) (Hobart et al., 2013). Also when treated with SR-Fampridine Coleman et al. (2012) estimated the MCID of the T25FW to be 17.2%. Blum et al. (2006) estimated the SDMT had an MCID of 5.1 a.u. We have not been able to find valid MCIDs for the SSST, the 9-HPT and the 5-STS, though Møller et al. (2012) reported a change of 25.5% to be a minimal reliable change for the latter. The objective of this short report is to estimate the MCID in measures of cognition (SDMT) and upper and lower body functional capacity (9-HPT, T25FW, SSST, 5-STS) after SR-Fampridine treatment in PwMS on the basis of previous studies
2.1. Study design
This study was designed as an open label explorative study investigating the effect of SR-Fampridine in different domains. Main results have been published previously (Jensen et al., 2014). This study was performed in accordance with the Declaration of Helsinki and monitored by the GCP-unit at Odense University Hospital, Denmark. The protocol and all study conditions were approved by The Regional Scientific Ethical Committees for Southern Denmark (journal number, S-20120023), and by the Danish Medical Agency (journal number, 2,012,012,850).
2.2. Inclusion and exclusion criteria
Eligible patients should meet the 2010 McDonald criteria for MS, be aged 18–60, have an EDSS between 4 and 7 with a pyramidal sub score of ≥2. Exclusion criteria were a history of epileptic seizures, change in immunodolutary treatment or MS relapse within 60 days, cancer within 5 years, clinically important systemic disease and concomitant treatment with cimetidine, carvedilol, propranolol or metformin.
2.3. Patient selection
In total 124 eligible patients were identified. 14 did not fulfill the inclusion criteria. Two did not give informed consent. 108 participants were included. Three participants did not complete the study, two due to adverse events, one due to a relapse. Thus data from 105 participants were analysed. Participants were treated with SR-Fampridine 10 mg bid for 4 weeks. Before initiating treatment, participants underwent testing by T25FW, SDMT, SSST, 9-HPT, and 5-STS which were repeated on day 26–28.
The MCID can be determined from a distribution-based method and an anchor-based method. In the distribution-based method MCID is estimated from its standard error of measurement (SEM), which is an estimate of the SD from multiple measurements in the same individual. From empirical evidence 1×SEM seems to be a good approximation of the MCID (Hobart et al., 2013). In the anchor-based method the change on a given clinical test is compared to a known MCID of another test, the anchor, preferably a Patient Related Outcome Measure.
2.4. Statistical methods
STATA 13 was used for data analysis. MCID was determined as 1×SEM (Hobart et al., 2013). SEM was calculated by SEM=✓(1−r)×SD, where r represented the test retest reliability here defined as the Intraclass Correlation Coefficient (ICC) with clusters being participants in whom measurements were made, and the observations within clusters were the repeated measurements on the individuals, and hence the ICC was calculated by Large One-Way ANOVA. The standard deviation (SD) was derived from pre-treatment values.
Mean age was 48.6±7.1 years, 58.3% were women, mean EDSS was 5.6±0.9 and mean disease duration was 10.8±7.2 years.
As presented in Table 1 MCID/SEM values were estimated for the T25FW to be 1.3 s (0.8–1.6), for the SDMT 5.0 a.u. (3.3–6.2), for the SSST 2.0 s (1.2–2.6), for the 9-HPT 3.0 s (0.0–4.3), and for the 5-STS 3.7 s (2.3–4.7). This corresponds to percentage MCID values of 14.2% (9.1–17.8) on the T25FW, 13.7% (9.2–17.1) on the SDMT, 14.7% (8.5–16.7) on the SSST, 10.7% (0.0–15.3) on the 9-HPT, and 27.3% (16.9–34.6) on the 5-STS (see Table 1).
|Pre-treatment||Post-treatment||r (ICC)||MCID||Percentage MCID|
|SDMT (a.u.) Range||37.6 (±12.8)||39.1 (±13.2)||0.85 (0.76–0.93)||5.0 (3.3–6.2)||13.7% (9.2–17.1)|
|9-HPT (s) range||29.7 (±9.7)||27.9 (±10.0)||0.91 (0.81–1.0)||3.0 (0.0–4.3)||10.7% (0–15.3)|
|T25FW (s) Range||10.3 (±8.1)||9.04 (±8.1)||0.98 (0.96–0.99)||1.3 (0.8–1.6)||14.2% (9.1–17.8)|
|SSST (s) range||19.0 (±11.4)||15.6 (±11.4)||0.97 (0.95–0.99)||2.0 (1.2–2.6)||14.7% (8.5–16.7)|
|5-STS (s) range||17.4 (±9.2)||13.6 (±5.0)||0.84 (0.74–0.94)||3.7 (2.3–4.7)||27.3% (16.9–34.6)|
The present study estimates distribution-based MCID values for the 9-HPT, the SSST and the 5-STS, and confirms previous MCID estimates on the T25FW and the SDMT. Ranges (95% CI) of the estimates were considered to be the borderline area of meaningful change (Hobart et al., 2013). Therefore the upper range set the highest threshold a patient under treatment with SR-Fampridine had to undergo in order to have 95% probability of having a clinically meaningful improvement.
Our estimated MCID of the SDMT of 6.2 a.u. was somewhat higher than the 5.1 a.u. suggested by Blum et al. (2006), though our point estimate was 5.0 a.u. MCIDs of the 9-HPT and the SSST were estimated at 15.3%, and 16.7% respectively. Our estimated MCID of the T25FW of 17.8% was in line with the estimated 17.2% of Coleman et al. (2012) and close to the MCID of >20% suggested by Hobart et al. (2013).
Our upper range regarding the 5-STS of 34.6% was somewhat higher than that of 25.5% estimated by Moller et al. (2012). However, our point estimate of 27.3% was in line with their findings. It is debatable whether our data represent valid MCID values, as they are not corroborated by an anchor-based method. The MCID estimates of the T25FW, the SDMT and the 5-STS are in line with previous findings, which support the validity of the estimate.
Our estimated MCIDs were purely distribution-based and therefore might not be generalizable. Our findings need to be corroborated by an anchor-based method. An appropriate anchor for the T25FW and the SSST would be the MSWS-12.
This study presents distribution-based estimates of MCID values for the SSST, the 9-HPT, and the 5-STS and confirms previous estimates for the T25FW and the SDMT. We find it of great importance to take MCID values into account when interpreting intervention effects in future studies in PwMS.
This study was funded by a research grant from the Region of Southern Denmark and a grant from The Research Fund of the MS-Clinic of Southern Jutland (Sønderborg, Vejle, Esbjerg) and an unrestricted research grant from Biogen Idec.
Biogen Idec supplied Fampyra tablets and placebo tablets.
Biogen Idec had no influence on design or execution of the study. Nor did Biogen Idec have influence on interpretation of or decision to publish the results.
Declaration of conflicting interests
HBJ has received research support from Biogen Idec and travel grants and/or teaching honoraries from Biogen Idec, Novartis, Almirall and Merck Serono and serves as an advisory board member for Novartis.
SM has no conflicting interests.
MR has received travel grants and consultancy honoraries from Biogen Idec, Genzyme, TEVA and Novartis and serves as an advisory board member for Biogen Idec.
UD has received research support, travel grants and/or teaching honoraries from Biogen Idec, Merck Serono and Sanofi Aventis. UD served as PI for the Biogen Idec sponsored ACTIMS study.
PA has no conflicting interests.
ES has received unrestricted research grants and travel support from Biogen Idec, Merck Serono and Bayer Schering and travel grants from Novartis.
The authors wish to thank the study nurses Margit Lund-Cramer, Helle Willer Christensen, Rikke Bjerre Rosengreen, Sarah Nielsen and Susanne Aabling for invaluable help.
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a Institute of Regional Health Research, University of Southern Denmark, Denmark
b MS-Clinic of Southern Jutland (Sønderborg, Vejle, Esbjerg), Department of Neurology, Sønderborg Hospital, Denmark
c Department of Neurology, Odense University Hospital, Denmark
d Department of Public Health, Section of Sport Science, Aarhus University, Denmark
⁎ Corresponding author at: Institute of Regional Health Research, University of Southern Denmark, J.B. Winsløws Vej 19.3, 5000 Odense C, Denmark.
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