Clinical Trials Register

Summary
EudraCT Number:	2010-021850-20
Sponsor's Protocol Code Number:	LMS-002
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-05-24
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2010-021850-20

A.3

Full title of the trial

A Phase 3, Multicenter, Double-Blind, Placebo-Controlled Randomized Discontinuation Study Followed by an Open-label Extension Period to Evaluate the Efficacy and Safety of Amifampridine Phosphate (3,4-
Diaminopyridine Phosphate) in Subjects with Lambert-Eaton Myasthenic Syndrome (LEMS)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Multicenter, double-blind, placebo-controlled, Randomized phase III study with an open phase extension of amifampridine phosphate (3,4-Diaminopyridine Phosphate) in patients with Lambert-Eaton myasthenic syndrome (LEMS)

A.4.1

Sponsor's protocol code number

LMS-002

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Catalyst Pharmaceutical Partners, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Catalyst Pharmaceutical Partners, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Catalyst Pharmaceutical Partners, Inc.
B.5.2	Functional name of contact point	Regulatory Operations
B.5.3	Address:
B.5.3.1	Street Address	355 Alhambra Circle, Suite 1500
B.5.3.2	Town/ city	Coral Gables
B.5.3.3	Post code	FL 33134
B.5.3.4	Country	United States
B.5.4	Telephone number	+1305529-2522
B.5.5	Fax number	+1305529-0933
B.5.6	E-mail	dwinship@catalystpharma.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	FIRDAPSE 10mg Tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	BioMarin Europe Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/02/124
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Amifampridine
D.3.9.1	CAS number	54-96-6
D.3.9.2	Current sponsor code	BioMarin Part Number: T1801
D.3.9.3	Other descriptive name	3,4-Diaminopyridine phosphate
D.3.9.4	EV Substance Code	SUB28846
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Lambert-Eaton Myasthenic Syndrome (LEMS)

E.1.1.1

Medical condition in easily understood language

Lambert-Eaton myasthenic syndrome (LEMS) in adults is a disease in which patients have muscle weakness

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10067685
E.1.2	Term	Lambert-Eaton myasthenic syndrome
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

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

E.2.3

Trial contains a sub-study

E.3

Principal 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.

E.4

Principal 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 the study. Male patients with breastfeeding partners are not excluded from the study.
•Likely or expected to require treatment for cancer within 3 months (90 days) after entering Screening.
•History of severe renal impairment or evidence of severe renal impairment on Screening laboratory tests
•Screening laboratory tests for hepatic impairment;
- In patients without cancer, ALT, AST, and/or total bilirubin > upper limit of normal (ULN)
- In patients with cancer, ALT/AST > 5x ULN and/or total bilirubin > 3x ULN.
•Any condition that, in the view of the investigator, places the patient at high risk of poor treatment compliance or of not completing the study.
•History of uncontrolled asthma, defined as 3 or more emergency room visits or hospitalizations in the 12 months prior to Screening due to asthma; or currently waking at night with asthma symptoms; or the need for quick-relief medication such as albuterol more than twice a week for asthma symptoms. Patients must be explicitly asked about any history of asthma as part of the Screening interview for entry into the study. History of mild to moderate asthma is allowed provided the patient is informed that exacerbations of asthma have been reported to occur following treatment with amifampridine.
• Forced vital capacity (FVC) < 1500 mL at Screening.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the change from baseline to Day 14 in QMG score.

E.5.1.1

Timepoint(s) of evaluation of this end point

0-14

E.5.2

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

E.5.2.1

Timepoint(s) of evaluation of this end point

0-14

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Followed by an Open-label Extension Period to Evaluate the Continued Efficacy and Safety

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Bulgaria

Canada

Chile

Czech Republic

France

Germany

Hungary

Italy

Poland

Russian Federation

Serbia

Spain

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The definition of the end of trial is last visit of the last subject completing 2 year follow up treatment period.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Upon completion of the trial patients will receive the expected normal treatment for their condition.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2011-09-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-09-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-07-06

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IMP with orphan designation in the indication
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