A Phase 3 Study of Amifampridine Phosphate in Patients With Lambert Eaton Myasthenic Syndrome (LEMS)

• Sponsor: Catalyst Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01377922
• Collaborator: (none)
• Enrollment: 38
• Locations: 14
• Arms: 2
• Duration (Months): 61
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

A Phase 3 study to evaluate the efficacy and safety of Amifampridine Phosphate in patients with Lambert-Eaton Myasthenic Syndrome (LEMS).

Condition or Disease	Intervention/Treatment	Phase
Lambert Eaton Myasthenic Syndrome	Drug: Amifampridine Phosphate; Drug: Placebo	Phase 3

Detailed Description

This multicenter, double-blind, placebo-controlled, randomized (1:1) discontinuation study is a 4-part study designed to evaluate the efficacy and safety of multiple dose administration of amifampridine phosphate in patients with LEMS. Data from parts 2 and 3 (the double-blind parts of the study) are presented in this record.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Double-blind, Placebo-controlled, Randomized Discontinuation Study Followed by Open-label Extension Evaluating Efficacy and Safety of Amifampridine Phosphate in Patients With Lambert-Eaton Myasthenic Syndrome (LEMS)
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Jul 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Matching placebo tablets administered 3-4 times a day (to the individual patient's tablet count of active at baseline) over 2 weeks.	Drug: Placebo; Matching placebo tablets administered 3-4 times a day (to the individual patient's tablet count of active at baseline) over 2 weeks.
Experimental: Amifampridine Phosphate Amifampridine, 30-80 mg given 3-4 times per day with a maximum single dose of 20 mg (2 x 10 mg tablets), for 2 weeks.	Drug: Amifampridine Phosphate; Amifampridine, 30-80 mg given 3-4 times per day with a maximum single dose of 20 mg (2 x 10 mg tablets), for 2 weeks.; Other Names: 3,4-diaminopyridine phosphate 3,4-DAP phosphate

Outcome Measures

Primary Outcome Measures

1. Change From Baseline Quantitative Myasthenia Gravis (QMG) at 14 Days [Assessment at Baseline and Day 14]

   The QMG is a physician-rated test including 13 assessments, including facial strength, swallowing, grip strength, and duration of time that limbs can be maintained in outstretched positions. Each of the 13 items is scored from 0 (none) to 3 (severe). The total score can range from 0 to 39. Increased QMG total score correlates to worsening symptoms of LEMS.

2. Change in SGI Score [Assessment at Baseline and Day 14]

   Subject Global Impression (SGI) is a measure of changes in subject's perception of change in overall wellbeing. The patient is asked to use the 7-point scale below to rate their impression of the effects of the study medication during the preceding 3 days on their physical well being. Terrible Mostly dissatisfied Mixed Partially satisfied Mostly satisfied Pleased Delighted

Secondary Outcome Measures

1. Change From Baseline Timed 25 Foot Walking Test (T25FW) at 14 Days [Assessment at Baseline and Day 14]

   The T25FW test, a component of the Multiple Sclerosis Functional Composite, was a quantitative mobility and leg function performance test based on a timed 25-foot walk (National Multiple Sclerosis Society). The patient was directed to walk a clearly marked 25-foot course as quickly and safely as possible. Following a rest of at least 5 minutes, the timed 25-foot walk was repeated. Patients could use assistive devices, such as canes, crutches, or walkers. All data were normalized to the number of feet per minute, so if the patient walked 25 feet in less than a minute, the result was a speed greater than 25 feet/minute. The measurement for the T25FW test was the average speed, expressed in feet/minute, of the 2 completed walks.

2. Change in CGI-I Score [Baseline and Day 14]

   The Investigator completed the 7-point CGI I, based on changes in symptoms, behavior, and functional abilities, at the protocol-specified time points compared to the patient's condition at Day 0. = Very much improved = Much improved = Minimally improved = No change = Minimally worse = Much worse = Very much worse

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria: Individuals eligible to participate in this study must meet all of the following inclusion criteria:

• ≥18 years of age

• Confirmed diagnosis of LEMS

• Normal respiratory function

• Normal swallowing function

• If receiving peripherally acting cholinesterase inhibitors a stable dose is required for at least 7 days prior to Screening.

• If receiving oral immunosuppressants a stable dose is required for at least 90 days prior to Screening.

• Negative pregnancy test for females of childbearing potential

• If sexually active, willing to use 2 acceptable methods of contraception

• 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 research-related procedures.

Exclusion Criteria: Individuals who meet any of the following exclusion criteria are not eligible to participate in the study:

• History of epilepsy or seizure.

• Known active brain metastasis.

• Use of Fampridine (4-aminopyridine), and any form of 3,4-diaminopyridine other than the IP provided, such as amifampridine base or Firdapse, during the study.

• Use of medications known to lower the epileptic threshold within 7 days or 5 half-lives.

• Use of medications which inhibit neuromuscular junction function within 7 days or 5 half-lives.

• Use of IVIG, plasmapheresis (plasma exchange), or immunoadsorption within 90 days

• Use of guanidine hydrochloride within 7 days

• Use of rituximab within 12 months

• History of drug allergy to any pyridine-containing substances or any amifampridine phosphate excipient(s).

• Use of any other investigational productwithin 30 days

• Treatment with a concomitant medication that prolongs the QT/QTc interval within 7 days or 5 half-lives.

• Treatment with sultopride (4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-ethylsulfonyl-2-methoxybenzamide) within 7 days.

• An abnormal electrocardiogram (ECG).

• Documented history of arrhythmias.

• History of additional risk factors for torsade de pointes.

• Breastfeeding or pregnant or planning to become pregnant (self or partner) at any time during the study.

• Likely or expected to require treatment for cancer within 3 months (90 days) after entering.

• History of severe renal impairment or evidence of severe renal impairment

• Any condition that places the patient at high risk of poor treatment compliance or of not completing the study.

• History of uncontrolled asthma.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States	35233
2		Scottsdale	Arizona	United States	85258
3		Los Angeles	California	United States	90095
4		Palo Alto	California	United States	94305
5		Kansas City	Kansas	United States	66160
6		New York	New York	United States	10032
7		Lyon		France	69677
8		Munich	Bavaria	Germany	D-80336
9		Berlin		Germany	D-10117
10		Pecs		Hungary	H-7623
11		Warsaw		Poland	02 097
12		Moscow		Russian Federation	125367
13		Belgrade		Serbia	11000
14		Madrid		Spain	28007

Sponsors and Collaborators

• Catalyst Pharmaceuticals, Inc.

Investigators

• Study Director: Charles W Gorodetzky, MD, PhD, Chief Medical Officer

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Catalyst Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01377922
• Other Study ID Numbers: LMS-002
• First Posted: Jun 22, 2011
• Last Update Posted: Jan 4, 2018
• Last Verified: Jan 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Lambert-Eaton Myasthenic Syndrome; Syndrome; Amifampridine

Study Results

Participant Flow

Recruitment Details	The study was conducted at 13 clinical sites in 8 countries, including France, Germany, Hungary, Poland, Russia, Serbia, Spain, and the United States. The study was conducted from 03Jun2011 to 08Jul2016.
Pre-assignment Detail	Open-label Run-in (Part 1): titration to the optimal amifampridine dose (well tolerated and resulted in a ≥3 point improvement in QMG score from Screening for patients without previous amifampridine use) for each individual patient. Patients who did not receive amifampridine prior to Run-in and who did not reach the optimal dose were discontinued.

Arm/Group Title	Part 2 and Part 3 Placebo	Part 2 and Part 3 Amifampridine Phosphate
Arm/Group Description	Matching placebo tablets, administered 3-4 times a day for 2 weeks. Placebo tablets indistinguishable from amifampridine phosphate tablets. The placebo was administered consistent with the dose and dose regimen of amifampridine phosphate.	Matching amifampridine phosphate tablets, 10 mg, administered 3-4 times a day for 2 weeks. Amifampridine Phosphate: 30-80 mg given 3-4 times per day with a maximum single dose of 20 mg (2 x 10 mg tablets).
Period Title: Overall Study
STARTED	22	16
COMPLETED	21	16
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Part 2 and Part 3 Placebo	Part 2 and Part 3 Amifampridine Phosphate	Total
Arm/Group Description	Matching placebo tablets, administered 3-4 times a day for 2 weeks. Placebo tablets indistinguishable from amifampridine phosphate tablets. The placebo was administered consistent with the dose and dose regimen of amifampridine phosphate.	Matching amifampridine phosphate tablets, 10 mg, administered 3-4 times a day for 2 weeks. Amifampridine Phosphate: 30-80 mg given 3-4 times per day with a maximum single dose of 20 mg (2 x 10 mg tablets).	Total of all reporting groups
Overall Participants	22	16	38
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.5 (17.57)	51.6 (12.05)	51.5 (15.30)
Sex: Female, Male (Count of Participants)
Female	14 63.6%	9 56.3%	23 60.5%
Male	8 36.4%	7 43.8%	15 39.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	3 18.8%	3 7.9%
Not Hispanic or Latino	22 100%	12 75%	34 89.5%
Unknown or Not Reported	0 0%	1 6.3%	1 2.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	21 95.5%	13 81.3%	34 89.5%
More than one race	0 0%	2 12.5%	2 5.3%
Unknown or Not Reported	1 4.5%	1 6.3%	2 5.3%
Was the patient taking amifampridine (base or phosphate) immediately prior to enrollment? (Count of Participants)
Yes	7 31.8%	3 18.8%	10 26.3%
No	15 68.2%	13 81.3%	28 73.7%
If yes, number of continuous days of amifampridine exposure immediately prior to enrollment (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	1287.1 (1525.73)	2143.3 (3080.16)	1544.0 (1957.36)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline Quantitative Myasthenia Gravis (QMG) at 14 Days
Description	The QMG is a physician-rated test including 13 assessments, including facial strength, swallowing, grip strength, and duration of time that limbs can be maintained in outstretched positions. Each of the 13 items is scored from 0 (none) to 3 (severe). The total score can range from 0 to 39. Increased QMG total score correlates to worsening symptoms of LEMS.
Time Frame	Assessment at Baseline and Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Amifampridine Phosphate
Arm/Group Description	Matching placebo tablets administered 3-4 times a day over 2 weeks. Placebo: Matching number of tablets to the individual patient's tablet count of active at baseline.	Matching amifampridine phosphate tablets, 10 mg, administered 3-4 times a day for 2 weeks. Amifampridine Phosphate: 30-80 mg given 3-4 times per day with a maximum single dose of 20 mg (2 x 10 mg tablets).
Measure Participants	21	16
Baseline	5.6 (3.99)	6.4 (3.22)
Day 14	7.9 (2.85)	6.7 (4.09)
Change from Baseline	2.2 (2.93)	0.3 (2.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Amifampridine Phosphate
	Comments
	Type of Statistical Test	Other
	Comments	Estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline QMG score as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
Statistical Test of Hypothesis	p-Value	0.0452
	Comments
	Method	Mixed Models Analysis
	Comments	Pairwise contrast at Day 14 from MMRM model.

2. Primary Outcome

Title	Change in SGI Score
Description	Subject Global Impression (SGI) is a measure of changes in subject's perception of change in overall wellbeing. The patient is asked to use the 7-point scale below to rate their impression of the effects of the study medication during the preceding 3 days on their physical well being. Terrible Mostly dissatisfied Mixed Partially satisfied Mostly satisfied Pleased Delighted
Time Frame	Assessment at Baseline and Day 14

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Placebo	Amifampridine Phosphate
Arm/Group Description	Matching placebo tablets administered 3-4 times a day over 2 weeks. Placebo: Matching number of tablets to the individual patient's tablet count of active at baseline.	Matching amifampridine phosphate tablets, 10 mg, administered 3-4 times a day for 2 weeks. Amifampridine Phosphate: 30-80 mg given 3-4 times per day with a maximum single dose of 20 mg (2 x 10 mg tablets).
Measure Participants	21	16
Baseline	5.9 (1.22)	5.6 (1.26)
Day 14	3.2 (1.7)	4.9 (1.57)
Change from Baseline	-2.7 (2.29)	-0.7 (1.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Amifampridine Phosphate
	Comments	Estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline SGI score as fixed effects and patient as a random effect. The model assumed time effect to be random between patients
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0028
	Comments	Pairwise contrast at Day 14 from MMRM model.
	Method	Mixed Models Analysis
	Comments

3. Secondary Outcome

Title	Change From Baseline Timed 25 Foot Walking Test (T25FW) at 14 Days
Description	The T25FW test, a component of the Multiple Sclerosis Functional Composite, was a quantitative mobility and leg function performance test based on a timed 25-foot walk (National Multiple Sclerosis Society). The patient was directed to walk a clearly marked 25-foot course as quickly and safely as possible. Following a rest of at least 5 minutes, the timed 25-foot walk was repeated. Patients could use assistive devices, such as canes, crutches, or walkers. All data were normalized to the number of feet per minute, so if the patient walked 25 feet in less than a minute, the result was a speed greater than 25 feet/minute. The measurement for the T25FW test was the average speed, expressed in feet/minute, of the 2 completed walks.
Time Frame	Assessment at Baseline and Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Amifampridine Phosphate
Arm/Group Description	Matching placebo tablets administered 3-4 times a day over 2 weeks. Placebo: Matching number of tablets to the individual patient's tablet count of active at baseline.	Matching amifampridine phosphate tablets, 10 mg, administered 3-4 times a day for 2 weeks. Amifampridine Phosphate: 30-80 mg given 3-4 times per day with a maximum single dose of 20 mg (2 x 10 mg tablets).
Measure Participants	21	16
Baseline	255 (111)	254 (126)
Day 14	244 (116)	253 (126)
Change from Baseline	-10.4 (53.1)	-1.46 (52.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Amifampridine Phosphate
	Comments	Estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction, and double-blind baseline T25FW walking speed as fixed effects and patient as a random effect. The model assumed time effect to be random between patients.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6274
	Comments
	Method	Mixed Models Analysis
	Comments

4. Secondary Outcome

Title	Change in CGI-I Score
Description	The Investigator completed the 7-point CGI I, based on changes in symptoms, behavior, and functional abilities, at the protocol-specified time points compared to the patient's condition at Day 0. = Very much improved = Much improved = Minimally improved = No change = Minimally worse = Much worse = Very much worse
Time Frame	Baseline and Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Amifampridine Phosphate
Arm/Group Description	Matching placebo tablets administered 3-4 times a day over 2 weeks. Placebo: Matching number of tablets to the individual patient's tablet count of active at baseline.	Matching amifampridine phosphate tablets, 10 mg, administered 3-4 times a day for 2 weeks. Amifampridine Phosphate: 30-80 mg given 3-4 times per day with a maximum single dose of 20 mg (2 x 10 mg tablets).
Measure Participants	21	16
Baseline	2.5 (0.98)	2.6 (0.63)
Day 14	4.8 (1.45)	3.6 (1.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Amifampridine Phosphate
	Comments	Estimated via a MMRM with change from baseline (Day 1, Part 2), Day 8, and Day 14 as the dependent variable and terms for treatment, time (Day 8, Day 14), treatment-by-time interaction as fixed effects and patient as a random effect. The model assumed time effect to be random between patients
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0267
	Comments
	Method	Mixed Models Analysis
	Comments

Adverse Events

Time Frame	The reporting period for non-serious AEs was the first administration of study drug through the termination visit or at the early termination visit. The reporting period for SAEs began after a signed ICF was obtained and continued through 4 weeks after the last dose or at the early termination visit.
Adverse Event Reporting Description	For this study, the following additional events were considered SAEs: A generalized tonic-clonic convulsion/seizure; A normal liver function test for a patient at Screening, but the patient developed the following constellation of findings: ALT or AST >3 times the ULN; total bilirubin >2 times the ULN; and no other explanation, such as concurrent liver disease or treatment with a potentially hepatotoxic concurrent medication, was found.
Arm/Group Title	Part 2 and Part 3 Placebo		Part 2 and Part 3 Amifampridine Phosphate
Arm/Group Description	Matching placebo tablets, administered 3-4 times a day for 2 weeks. Placebo tablets indistinguishable from amifampridine phosphate tablets. The placebo was administered consistent with the dose and dose regimen of amifampridine phosphate.		Matching amifampridine phosphate tablets, 10 mg, administered 3-4 times a day for 2 weeks. Amifampridine Phosphate: 30-80 mg given 3-4 times per day with a maximum single dose of 20 mg (2 x 10 mg tablets).
All Cause Mortality
	Part 2 and Part 3 Placebo		Part 2 and Part 3 Amifampridine Phosphate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/16 (0%)
Serious Adverse Events
	Part 2 and Part 3 Placebo		Part 2 and Part 3 Amifampridine Phosphate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Part 2 and Part 3 Placebo		Part 2 and Part 3 Amifampridine Phosphate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/21 (28.6%)		3/16 (18.8%)
General disorders
Asthenia	2/21 (9.5%)		0/16 (0%)
Fatigue	1/21 (4.8%)		1/16 (6.3%)
Infections and infestations
Nasopharyngitis	0/21 (0%)		1/16 (6.3%)
Otitis externa	0/21 (0%)		1/16 (6.3%)
Periodontitis	1/21 (4.8%)		0/16 (0%)
Pulpitis dental	1/21 (4.8%)		0/16 (0%)
Urinary tract infection	0/21 (0%)		1/16 (6.3%)
Investigations
Blood creatine phosphokinase increased	1/21 (4.8%)		0/16 (0%)
Musculoskeletal and connective tissue disorders
Muscular weakness	1/21 (4.8%)		0/16 (0%)
Sensation of heaviness	1/21 (4.8%)		0/16 (0%)
Psychiatric disorders
Depression	1/21 (4.8%)		0/16 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/21 (4.8%)		0/16 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.