Lambert-Eaton Myasthenic Syndrome (LEMS) MedDRA version: 14.1 Level: LLT Classification code 10067685 Term: Lambert-Eaton myasthenic syndrome System Organ Class: 100000004852
Conditions
Interventions
Trade Name: FIRDAPSE 10mg Tablets
Pharmaceutical Form: Tablet
INN or Proposed INN: Amifampridine
CAS Number: 54-96-6
Current Sponsor code: BioMarin Part Number: T1801
Other descriptive name: 3,4-Diami
Sponsors
Catalyst Pharmaceutical Partners, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • =18 years of age. • Confirmed diagnosis of LEMS as documented by acquired (typical) proximal muscle weakness and at least 1 of the following: o Nerve conduction findings (CMAP that increases at least 2-fold after maximum voluntary contraction of the tested muscle) o Positive anti-P/Q type voltage-gated calcium-channel antibody test • If currently receiving treatment with amifampridine for LEMS, a normal respiratory function as defined by an FVC = 80% of predicted. • If not currently receiving treatment with amifampridine for LEMS and patient has no history of other current respiratory disease, an FVC of = 60% of predicted. • Normal swallowing function as defined by the ability to swallow 4 ounces of water without coughing or throat clearing (score of 0 on this dimension of QMG). • Completion of anti-cancer treatment at least 3 months (90 days) prior to Screening. • A QMG score of = 5 is required for patients without any prior symptomatic treatment for LEMS. • If currently receiving treatment for LEMS, patients must present with some signs and/or symptoms consistent with LEMS. • If receiving peripherally acting cholinesterase inhibitors (eg, pyridostigmine), a stable dose of cholinesterase inhibitors is required for at least 7 days prior to Screening. • If receiving permitted oral immunosuppressants (eg, prednisone or other corticosteroid, azathioprine, mycophenolate), a stable dose is required for at least 90 days prior to Screening. • Negative pregnancy test for females of childbearing potential at Screening. • If sexually active, willing to use 2 acceptable methods of contraception from Screening until 3 months after the last dose. • Willing to perform all study procedures as physically possible. • Willing and able to provide written informed consent after the nature of the study has been explained and prior to the start of any researchrelated procedures. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 46 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 33
Exclusion criteria
Exclusion criteria: • History of epilepsy or seizure (including 1 time seizure, but excluding generalized febrile seizures occurring before the age of 5 years). •Known active brain metastasis. Patients with treated brain metastasis (radiotherapy and /or surgery) who have completed treatment for their brain metastasis > 90 days prior to Screening, are neurologically stable (neurological symptoms grade = 1), are on a stable dose of corticosteroids, and have no evidence of new disease on magnetic resonance imaging (MRI), are eligible provided they meet the other inclusion/exclusion of the study. •Concurrent use of fampridine (4-aminopyridine), and any form of 3,4 diaminopyridine other than the IP provided, such as amifampridine base or FirdapseTM, during the study. •Use of medications known to lower the epileptic threshold (eg, antidepressants such as tricyclics and bupropion; neuroleptics such as phenothiazines, butyrophenones, clozapine, olanzapine, quetiapine; immunosuppressants such as cyclosporine, tacrolimus; centrally active cholinesterase inhibitors such as donepezil, rivastigmine, galantamine; mefloquine) within 7 days or 5 half-lives, whichever is longer, prior to Screening. - Selected antidepressants of the selective serotonin uptake inhibitor (SSRI) class and tramadol are acceptable provided the dose regimen has been stable (not as needed) for > 90 days prior to Screening without evidence of seizure. •Use of medications which inhibit neuromuscular junction function within 7 days or 5 half-lives, whichever is longer, prior to Screening. •Use of intravenous immunoglobulin (IVIG), plasmapheresis (plasma exchange), or immunoadsorption within 90 days prior to Screening. •Use of guanidine hydrochloride within 7 days of Screening. •Use of rituximab within 12 months prior to Screening. •History of drug allergy to any pyridine-containing substances or any amifampridine phosphate excipient(s). •Use of any investigational product (other than amifampridine base or phosphate) or an investigational medical device within 30 days prior to Screening or requirement for any investigational agent prior to completion of all scheduled study assessments. •Treatment with a concomitant medication that prolongs the QT wave (QT)/ QT wave corrected for heart rate (QTc) interval within 7 days or 5 half-lives, whichever is longer, prior to Screening. •Treatment with sultopride (4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-ethylsulfonyl-2-methoxybenzamide) within 7 days prior to Screening. •An ECG at Screening that, in the opinion of the external reviewing cardiologist, shows any of the following: - Sinus arrhythmia with unacceptable rate variation (eg, > 20% RR variability) - Excessive heart rate variation at rest - QT wave corrected for heart rate using Bazett’s formula (QTcB) interval > 450 msec confirmed by a repeat ECG - PR interval > 210 msec - QRS interval > 120 msec if 35 years of age or younger, or > 110 msec if over 35 years - Early repolarization pattern that increases the risk of participating in the study. •Documented history of arrhythmias (eg, ventricular arrhythmias and atrial fibrillation). •History of additional risk factors for TdP (eg, history of surviving a near drowning due to loss of consciousness, family history of congenital QT syndrome, Long QT Syndrome, family history of unexplained early sudden death, heart failure). •Breastfeeding or pregnant at Screening or planning to become pregnant (self or partner) at any time during th
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Efficacy • To compare the efficacy of amifampridine phosphate versus placebo on muscle strength in patients with LEMS at the end of a 14-day discontinuation period Safety • To assess the safety, including the long-term safety, of amifampridine phosphate in patients with LEMS.;Secondary Objective: The secondary objective of the study is: • To compare the efficacy of amifampridine phosphate versus placeboon walking speed in patients with LEMS at the end of a 14-day discontinuation period The tertiary objectives of the study are: • To compare the efficacy of amifampridine phosphate versus placebo on the following parameters in patients with LEMS at the end of a 14-day discontinuation period: o CMAP: amplitude o CGI-S: Investigator-perceived improvement in illness severity o CGI-I: Investigator-perceived global improvement or change o SGI: Subject global impression of improvement The exploratory objectives of the study are: • To confirm the exposure of amifampridine and its major metabolite, 3- N-acetyl amifampridine, based on plasma concentrations in the LEMS patient population • To evaluate the relationship between NAT genetic polymorphism status and plasma levels of amifampridine and 3-N-acetyl amifampridine in LEMS patients;Primary end point(s): The primary efficacy endpoint is the change from baseline to Day 14 in QMG score.;Timepoint(s) of evaluation of this end point: 0-14 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary efficacy endpoint is the change from baseline to Day 14 in walking speed assessed by the T25FW test. Tertiary efficacy endpoints are: • Change from baseline to Day 14 in CMAP amplitude • The Day 14 CGI-I and SGI scale measurements • The proportion of patients in each treatment group with a Day 14 CGII scale rating of 1, 2, 3, or 4 • The proportion of patients in each treatment group with a Day 14 SGI scale rating of 4, 5, 6, or 7 • The change from baseline to Day 14 in CGI-S scale measurements;Timepoint(s) of evaluation of this end point: 0-14 | — |
Countries
Argentina, Bulgaria, Canada, Chile, Czech Republic, France, Germany, Hungary, Italy, Poland, Russian Federation, Serbia, Spain, United States
Contacts
Public ContactRegulatory Operations
Catalyst Pharmaceutical Partners, Inc.
Outcome results
None listed