Primary:The primary objective of Study 218MS305 is to determine whether prolonged-release fampridine (10 mg BID) has a clinically meaningful effect on patient-reported walking ability over a 24-week study period.Secondary:The secondary objectives…
ID
Source
Brief title
Condition
- Other condition
- Central nervous system infections and inflammations
Synonym
Health condition
nervous system disorders, movement disorders not including parkinsonism
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint in this study is the proportion of subjects who achieve a
mean improvement on the MSWS-12 of * 8 points from baseline over a 24-week
treatment period. -12 is <8 points at baseline, the subject will be counted as
having a point mean improvement from baseline if their mean MSWS-12 score
during the treatment period is <0.5. Baseline will be defined as the mean of
scores from Screening and Day 1 Visits. To determine whether a subject achieved
a mean improvement of at least 8 points, the mean change on MSWS-12 will be
calculated as the difference between the mean on-treatment score over 24 weeks
and the mean pretreatment score. The primary analysis will be performed in the
intent-to-treat (ITT) population and missing data will be handled using the
multiple imputation procedure [Schafer 1997; Schafer 1999]. Comparisons between
the fampridine and placebo treatment groups will be made using a logistic
regression model adjusted for the
baseline MSWS-12 score and the Screening EDSS score. Hypothesis testing will be
performed at a 2-sided 5% significance level. If an interim analysis is
performed, then hypothesis testing will be performed as described in the
protocol.
Secondary outcome
For the secondary endpoints, the proportion of subjects who achieve a mean
improvement in TUG speed of >15% from baseline over a 24-week period will be
compared between treatment groups using a logistic regression model adjustedfor
the baseline TUG speed and the Screening EDSS score. Baseline will be defined
as the mean speed over Screening and Day 1. The mean changes from baseline in
the
MSIS-29, BBS, and ABILHAND scores will be compared using an analysis of
covariance (ANCOVA) model adjusted for the corresponding baseline score and the
Screening EDSS score. Baseline for MSIS-29 and BBS scores will be defined as
the mean of scores from the Screening and Day 1 Visits. Baseline for the
ABILHAND score will be defined as the score on Day 1 Visit. Secondary efficacy
analyses on TUG speed, MSIS-29, BBS, and ABILHAND scores will be performed in
the ITT population and missing data will be handled using the multiple
imputation procedure [Schafer 1997; Schafer 1999]. Depending on the
distribution of data for changes from baseline in MSIS-29, BBS, and ABILHAND
scores, nonparametric analyses may be performed instead. Hypothesis testing
will be performed at a 2-sided 5% significance level overall, with adjustment
for testing multiple endpoints and the potential interim analysis. A
combination of the sequential step-down procedure and the Hochberg procedure
will be used to control the overall Type I error in the testing of secondary
efficacy endpoints. Analyses will also be performed to assess the predictive
values of different measures of early response. For the exploratory endpoints,
descriptive statistics will be used to summarize changes from Day 1 in
EQ-5D-3L, SF-36, Version 2 (EQ-5D-3L visual analogue score and index score, and
SF-36 subscale scores), and SDMT. If the data are normally distributed for
these endpoints, least square means and 95% confidence intervals will be
presented using an ANCOVA model adjusted for baseline and the Screening EDSS
score. Otherwise, nonparametric analyses will be used. The proportion of
subjects with an improvement on the PGIC and changes in HRU over time will also
be summarized. Incidence of AEs occurring within each treatment group will be
summarized overall, by severity, and by relationship to study treatment.
Incidence of SAEs will be summarized by treatment group. Actual values and
changes from baseline will be summarized by treatment group for laboratory
assessments
and vital signs. Laboratory assessments will also be summarized for each
treatment group using shift tables. Incidence of clinically meaningful changes
in vital signs and ECGs will be summarized by treatment group.
Background summary
MS is an inflammatory condition that damages the myelin of the central nervous
system and causes neurological impairment, often leading to severe disability.
Its etiology remains unknown, although it is generally assumed that MS is
mediated by an autoimmune process, possibly triggered by infection, and
superimposed upon a genetic predisposition. MS is the most common cause of
neurological disability in young and middle-aged adults and has a major
physical, psychological, social, and financial impact on patients and their
families. In particular, walking impairment is a prominent manifestation of MS.
Up to 85% of MS patients identify it as their primary complaint [Scheinberg
1980].
The prolonged-release formulation of fampridine (prolonged-release fampridine)
has been approved in the United States as a treatment to improve walking in
patients with MS (demonstrated by an increase in walking speed) under the
proprietary name Ampyra® since 22 January 2010. Fampridine has also been
approved under the brand name Fampyra® in the European Union (EU; July 2011)
and other countries. The United States Adopted Name (USAN) is The effectiveness
of prolonged-release fampridine 10 mg twice daily (BID), given 12 hours apart,
in improving walking in patients with MS was evaluated in 2 pivotal randomized,
placebo-controlled Phase 3 studies (MS-F203 and MS-F204) involving 540 subjects.
The primary measure of efficacy in both trials was walking speed (in feet per
second) as measured by the Timed 25-Foot Walk (T25FW), using a responder
analysis. A responder was defined as a subject who showed faster walking speed
for at least 3 out of a possible 4 visits during the double-blind treatment
period than the maximum value achieved in the 5 nontreatment visits (4 before
the double-blind period and 1 during the postdosing follow-up period).
During the double-blind treatment period, a significantly greater proportion of
subjects taking prolonged-release fampridine had increases in walking speed
compared with subjects taking placebo. In Study MS-F203, at least 50% of
fampridine-treated subjects had more than a 10% increase in walking speed from
baseline, at least 30% of the subjects had more than a 20% increase in walking
speed from baseline, and at least 10% of the subjects had more than a 30%
increase in walking speed from baseline, compared with a significantly lower
proportion of subjects taking placebo. A similar pattern was also observed in
Study MS-F204.
A recently completed Phase 2 study (218MS205) [n=132] assessed the effects of
prolonged-release fampridine 10 mg BID on MS subjects* self-assessed walking
disability and balance. The objectives of Study 218MS205 were to explore the
impact of prolonged-release fampridine on overall walking disability, and to
further elucidate the clinical relevance of changes over the 24-week treatment
duration. Using the patient global impression of change as well as other anchor
and distribution-based analyses, the minimum clinically important difference on
the Multiple Sclerosis Walking Scale 12 (MSWS-12) was estimated at 8 points for
improvement. Although formal statistical hypothesis testing was not performed
in this study, a larger proportion of fampridine-treated subjects had at least
an 8-point mean improvement on the MSWS-12, when compared with placebo-treated
subjects (48.5% and 28.1%,respectively). Fampridine-treated subjects also
exhibited improvements on the Timed Up and Go test (TUG), the Multiple
Sclerosis Impact Scale (MSIS-29) physical subscale, and the Berg Balance Scale
(BBS) as compared with placebo-treated subjects.
Study objective
Primary:
The primary objective of Study 218MS305 is to determine whether
prolonged-release fampridine (10 mg BID) has a clinically meaningful effect on
patient-reported walking ability over a 24-week study period.
Secondary:
The secondary objectives are as follows:
- To determine whether prolonged-release fampridine 10 mg BID has a clinically
meaningful effect on dynamic and static balance, physical impact of MS, and
upper extremity function over a 24-week study period
- To evaluate criteria for early assessment of response to fampridine that can
predict clinically meaningful benefits in walking ability and balance
- To assess the safety and tolerability of prolonged-release fampridine 10 mg
BID over a 24-week treatment period.
Study design
Subjects will be screened up to 14 days prior to Day 1. Eligible subjects will
be enrolled into the study and, after undergoing baseline assessments, will be
randomized in a 1:1 ratio to receive fampridine or placebo for 24 weeks.
Randomization will be stratified by the Expanded Disability Status Scale (EDSS)
score (*6 or >6) at Screening.
Assessments will be conducted at Weeks 2 and 4, and then every 4 weeks, until
the last study treatment is administered at the Week 24 Visit. Not all
assessments will be performed at every visit. A Follow-up Visit will be
conducted at 2 weeks (±3 days) following the last study treatment
administration (Week 24/Early Termination Visit).
Intervention
The treatment is to be self-administered by the subjects at home. Tablets must
be swallowed whole and must not be divided, crushed, dissolved, sucked, or
chewed. The tablets are to be taken without food, on an empty stomach. Water
should be used to aid in swallowing the tablet. The desiccant should not be
swallowed and, if removed, must be placed back into the bottle. Subjects are
expected to receive prolonged-release fampridine 10 mg BID or matched placebo
BID every 12 hours for up to 24 weeks.
Study burden and risks
For nature and extent of burden, please see the schedule of events section of
the protocol and section E4 of this form. For the risks please see section E9.
Regarding the benefit: it could be that prolonged-release fampridine (10 mg
BID) has a clinically meaningful effect on patient-reported walking ability.
However, there is no guarantee that the subjects condition will improve by
participation in this study. The results of the study might help people with a
similar condition in the future. It is possible that the symptoms of the
subjects condition will not improve during the study or may even worsen.
Treatment with this study drug may also involve risks to the subjects future
health that we currently don*t know about.
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Age
Inclusion criteria
1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations;2. Aged 18 to 70 years, inclusive, at the time of informed consent.;3. Female subjects of childbearing potential must have a negative urine pregnancy test at the Screening Visit and on Day 1. All subjects must agree to practice effective contraception during the study, and be willing and able to continue contraception for 30 days after their last dose of study treatment. For effective contraception methods, see Section 15.5.3.;4. Must have a diagnosis of primary-progressive, secondary-progressive, progressive-relapsing, or relapsing-remitting MS per revised McDonald Committee criteria [McDonald 2001; Polman 2005] as defined by Lublin and Reingold [Lublin and Reingold 1996] of at least 3 months duration.;5. Must have an EDSS score of 4 to 7, inclusive.;6. Must have walking impairment, as deemed by the Investigator.;7. Subjects must be able to understand and comply with the requirements of the protocol.
Exclusion criteria
1. History of human immunodeficiency virus (HIV).;2. Presence of acute or chronic hepatitis. Subjects who have evidence of prior hepatitis infection that has been serologically confirmed as resolved are not excluded from study participation.;3. Known allergy to fampridine, pyridine-containing substances, or any of the inactive ingredients in the prolonged-release fampridine tablet.;4. Any history of seizure, epilepsy, or other convulsive disorder, with the exception of febrile seizures in childhood.;5. CrCl of <80 mL/min.;6. History of malignant disease, including solid tumors and hematologic malignancies (with the exception of basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured) within the 5 years prior to the Screening Visit or at any time during the screening period.;7. Onset of MS exacerbation within 60 days prior to the Screening Visit, or at any time during the screening period.;8. History of any major surgical intervention (with the exception of skin biopsy) within the 30 days prior to the Screening Visit or Day 1, or at any time during the screening period.;9. Any non-MS-related condition or factor (as determined by the Investigator) that is likely to interfere with walking ability including, but not limited to, previous major surgery of the foot, leg, or hip; any significant trauma; or known peripheral neuropathy of the lower limb.;10. Presence of pulmonary disease including, but not limited to, chronic obstructive pulmonary disease that can impede the subject*s daily activities (as determined by the Investigator).;11. Presence of any psychiatric disorder, including clinical depression, that is likely to interfere with the subject*s participation in the study (as determined by the Investigator).;12. Uncontrolled hypertension (as determined by the Investigator) at the Screening Visit or at any time during the screening period.;13. History of any clinically significant cardiac, endocrinologic, hematologic, immunologic, metabolic, urologic, neurologic (except for MS, but including events indicative of a potentially lower seizure threshold), dermatologic, or other major disease (as determined by the Investigator).;14. Clinically significant abnormal laboratory values.;15. A body mass index (BMI) *40 (BMI formula: BMI = mass [kg]/[height(m)]2);16. History of severe allergic or anaphylactic reactions.;17. Use of off-label MS treatment including rituximab, daclizumab, or antibody (except natalizumab) within the 3 months prior to the Screening Visit, at any time during the screening period, or scheduled for use during study participation.;18. Use of mitoxantrone or cyclophosphamide within the 3 months prior to the Screening Visit, at any time during the screening period, or scheduled for use during study participation.;19. Initiation of natalizumab or alemtuzumab treatment or any change in the subject*s dose or regimen of natalizumab or alemtuzumab, within the 3 months prior to the Screening Visit, or at any time during the screening period.;20. Initiation of treatment with, or any change in the subject*s dose or regimen of, interferon *-1b, interferon *-1a, fingolimod, teriflunomide, glatiramer acetate, or dimethyl fumarate within the 30 days prior to the Screening Visit or at any time during the screening period.;21. Pulsed steroid treatment within the 60 days prior to the Screening Visit or at any time during the screening period.;22. Any change in the subject*s medication dose or regimen for the treatment of fatigue or depression within the 30 days prior to the Screening Visit or at any time during the screening period.;23. Any change in prophylactic treatment for pain with antidepressants or anticonvulsants prescribed for this purpose within 30 days prior to the Screening Visit or at any time during the screening period.;24. Any change in the subject*s dose or regimen of antispastic agents within the 7 days prior to the Screening Visit or at any time during the screening period.;25. Treatment with an investigational drug within the 30 days (or 7 half-lives, whichever is longer) prior to the Screening Visit or at any time during the screening period.;26. Treatment with any aminopyridine (fampridine, 4-AP, or 3,4-diaminopyridine [DAP] in any formulation) within the 30 days prior to the Screening Visit or at any time during the screening period.;27. Treatment with organic cation transporter 2 (OCT2) inhibitors within 5 half-lives prior to the Screening Visit or at any time during the screening period;28. History of drug or alcohol abuse within the 2 years prior to the Screening Visit.;29. Female subjects who are currently pregnant or who are considering becoming pregnant while participating in the study.;30. Female subjects who are currently breastfeeding.;31. Inability to comply with study requirements.;32. Subject who plan to participate in another clinical study (including any observational studies) during the course of the current study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-003600-40-NL |
| ClinicalTrials.gov | NCT02219932 |
| CCMO | NL50685.096.14 |