Version History. Previous Versions. Drugs for MS.Drug facts box fampridine Version 1.0 Author

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Version History

Policy Title Drugs for MS.Drug facts box – fampridine

Version 1.0

Author West Midlands Commissioning Support Unit

Publication Date Jan 2013

Review Date

Supersedes/New

(Further fields as required by local organisations)

Previous Versions

Version Date Changes

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Drugs for multiple sclerosis

Summaries of key information and evidence for efficacy and safety January 2013

Drug Facts Box for Fampridine-SR

What is this drug for?¹ Improvement of walking in adult patients with multiple sclerosis

Who is this drug for?¹ Adults with multiple sclerosis and a walking disability score of 4 to 7 on the EDSS (Expanded Disability Status Scale)

Who should not be taking this drug?¹

Patients under age 18

Patients with any severity of renal disease

Patients with prior history or current presentation of seizure How is this drug

administered?¹ Prolonged-release tablet What dose of this

drug is administered?¹

One 10 mg tablet How often is this drug

administered?¹

Twice daily (for two weeks, then need should be reassessed) What is the cost of

this drug?

One 28-tablet pack, sufficient for one patient for two weeks, costs £181 What are the adverse

reactions associated with this drug?

Most commonly: seizure, insomnia, anxiety, balance disorder, dizziness, paraesthesia, tremor, headache, asthenia and urinary tract infection

Licensing timeline Launched in the UK in July 2011

Other information:¹ Fampridine-SR should be given with caution to patients with cardiac rhythm or conduction disorders

Studies Summary of methods

Three double-blind, placebo-controlled, RCTs evaluated the efficacy of fampridine-SR as a treatment to improve walking speed in patients with MS. ^2,3,4 One trial was a phase 2 trial, assessed fampridine- SR at doses of 10, 15 or 20 mg twice daily [15 and 20 mg doses are unlicensed]; the other trials were phase 3 trials that assessed fampridine-SR 10 mg twice daily. Included patients had MS in a stable phase with an average EDSS of 5.8 and were able to complete two, 25-foot timed walk tests.

Following screening and a two-week placebo run-in period, the double-blind treatment phase lasted 9 to 14 weeks, with two to four weeks’ follow up. Patients were given 25-foot timed walk tests before, during and after treatment. The primary outcome measure in two trials was the number of patients who showed a response to treatment, defined as a faster walking speed for at least three of four 25- foot timed walk tests whilst on treatment compared with off-treatment periods. In the third trial, the primary outcome was the percentage change in walking speed. In this trial, response to treatment was measured in a post-hoc analysis. Other outcome measures across the trials were the 12-item multiple sclerosis walking scale (MSWS-12), the Ashworth score for spasticity, the lower extremity manual muscle test (LEMMT), and the subject’s and clinician’s global impression of change.

Quality of the trials

The design of the trials was fairly good, all three being double-blind, randomised and placebo controlled. However, the trials were marred by reporting most of the secondary outcomes in terms of responders and non-responders, which implied that efficacy was greater than from the actual results in the fampridine-treated versus the placebo-treated patients (these results are not included below).

Main results

In all three trials, significantly more fampridine-SR-treated patients showed a response to treatment than those receiving placebo (35 to 43% vs. 9%, p < 0.05). The improvement in mean walking speed

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from baseline was significantly greater with fampridine treatment than with placebo in two trials (p <

0.05). However, the improvements in mean walking speeds seen in the trials were not very large: 0.09 to 0.3 feet/second in fampridine-treated patients and 0.04 to 0.18 feet/second in placebo-treated patients.

Adverse events

The adverse events seen in the trials are described above.

References

1. Biogen Idec Ltd. Fampyra 10 mg prolonged-release tablets. EMC. 2012.

http://www.medicines.org.uk/EMC/medicine/25003/SPC/Fampyra+10+mg+prolonged- release+tablets/ <accessed 3/2012>

2. Goodman AD, Brown TR, Cohen JA et al. Dose comparison trial of sustained-release fampridine in multiple sclerosis. Neurology 2008;71:1134-41.

3. Goodman AD, Brown TR, Krupp LB et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet 2009;373:732-8.

4. Goodman AD, Brown TR, Edwards KR et al. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol 2010;68:494-502.

5. Fampyra Assessment Report (EMEA/H/C/002097). European Medicines Agency. 2011.

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-

_Public_assessment_report/human/002097/WC500109957.pdf <accessed 4/2012>

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4 Table 1. Fampridine: study design

Study

(n randomised)

Inclusion criteria Exclusion criteria Duration of study Treatment arms All doses given twice daily

Main outcomes Primary

Secondary MS-F202 (Goodman et al., 2008²)

Double-blind RCT Multicentre (24) n = 206

Jadad: 3

Funding: not stated but some authors were employees of the manufacturer

 Adults, aged 18 to 70

 Clinically defined multiple sclerosis

 Able to complete two trials of the timed 25-foot walk test (T25FW) in an average time of 8 to 60 seconds at screening

 Recent MS relapse

 Recent change in medication

1-week screening, 2-week single- blind placebo run- in, 2-week titration for higher doses groups, 12-week stable dose treatment period, 2-week follow up

Fampridine-SR 10 mg (52)

Placebo (47)

 Percentage change in walking speed during treatment relative to baseline using T25FW

 LEMMT

 Ashworth score for spasticity

 Patient and clinician global impression of change

 MSQLI

 MSWS-12

 Other multiple sclerosis functional composite components

MS-F203 (Goodman et al., 2009³) Double-blind RCT

Multicentre (33) n = 300

Jadad: 5

Company sponsored Funding: university

 Adults, aged 18 to 70

 Clinically defined multiple sclerosis

 Able to complete two trials of the T25FW in an average time of 8 to 45 seconds at screening

 Onset of MS exacerbation within 60 days of screening

 History of seizures or evidence of epileptiform activity on EEG

 Any condition that would interfere with study conduct

1-week screening, 2-week single- blind placebo run- in, 14 weeks’

double-blind treatment, 4-week follow up

Placebo (72)

 Response to treatment (faster walking speed in ≥ 3 of 4 assessment visits on treatment, compared with maximum speed assessed when not treated)

 12-item multiple sclerosis walking scale

 Patient and clinician global impression of change

 Ashworth score (average of three muscle groups)

 LEMMT (measured strength in four muscle groups)

 MSWS-12

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5 MS-F204 (Goodman et al.,2010⁴)

Double-blind RCT Multicentre (39) n = 239

Jadad: 4

Funding: company

As for MS-F203 above

1-week screening, 2-week single- blind placebo run- in, 9 weeks’

double-blind treatment, 4-week follow up

Placebo (119)

As for MS-F203 above

EEG, electroencephalogram; MS, multiple sclerosis; MSQLI, Multiple Sclerosis Quality of Life Inventory; MSWS-12, Multiple Sclerosis Walking Scale; RCT, randomised controlled trial; SD, standard deviation; T25FW, timed 25-foot walk test

Fampridine Table 2. Results (data taken from published articles with supplementary material from EMA assessment report for fampridine⁵) Outcomes:

Primary outcomes Secondary outcomes

MS-F202² (n = 206) MS-F203³ (n = 300) MS-F204⁴ (n = 239)

Placebo Fampridine-SR 10

mg Placebo Fampridine-SR 10 mg Placebo Fampridine-SR 10 mg Percentage of patients

who responded to treatment ^2-4

8.5% 35.3%† 8%

35%***

OR 4.75 (2.08 to 10.86)

9%

43%***

OR 8.14 (3.73 to 17.74) Average change in walking

speed from baseline in ft./second ± SE⁵ (baseline speed)

0.04 ± 0.077 (1.8)

0.09 ± 0.077 (1.83)

0.11 ± 0.066 (2.04)

0.3 ± 0.040*

(2.02)

0.18 ± 0.046 (2.21)

0.31 ± 0.046*

(2.12)

Average change in MSWS-

12 ± SD⁵ -1.84 ± 2.40 -4.63 ± 2.22 -0.08 ± 1.46 -2.84 ± 0.88 0.87 ± 1.22 -2.77 ± 1.20*

Change in LEMMT⁵ -0.04 0.11** 0.05 0.13* 0.05 0.1

* p < 0.05 vs. placebo, ** p < 0.001 vs. placebo; *** p < 0.0001 vs. placebo; † significant difference reported but no p value quoted;

CI, confidence interval; ft./s, feet per second; LEMMT, lower extremity manual muscle test; OR, odds ratio; MSWS-12, Multiple sclerosis walking scale;

SD, standard deviation; SE, standard error of the mean