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

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ClinicalTrials.gov Identifier: NCT01377922
Recruitment Status : Completed
First Posted : June 22, 2011
Results First Posted : January 4, 2018
Last Update Posted : January 4, 2018
Sponsor:
Information provided by (Responsible Party):
Catalyst Pharmaceuticals, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Lambert Eaton Myasthenic Syndrome
Interventions Drug: Amifampridine Phosphate
Drug: Placebo
Enrollment 38
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 Details 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
Hide 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
Reason Not Completed
rescue tx after part 2, entered part 4             1             0
Arm/Group Title Part 2 and Part 3 Placebo Part 2 and Part 3 Amifampridine Phosphate Total
Hide 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 Number of Baseline Participants 22 16 38
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 22 participants 16 participants 38 participants
51.5  (17.57) 51.6  (12.05) 51.5  (15.30)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants 16 participants 38 participants
Female
14
  63.6%
9
  56.3%
23
  60.5%
Male
8
  36.4%
7
  43.8%
15
  39.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants 16 participants 38 participants
Hispanic or Latino 0 3 3
Not Hispanic or Latino 22 12 34
Unknown or Not Reported 0 1 1
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants 16 participants 38 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
White
21
  95.5%
13
  81.3%
34
  89.5%
More than one race
0
   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?  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants 16 participants 38 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   [1] 
Mean (Standard Deviation)
Unit of measure:  Days
Number Analyzed 7 participants 3 participants 10 participants
1287.1  (1525.73) 2143.3  (3080.16) 1544.0  (1957.36)
[1]
Measure Analysis Population Description: Data only for those subjects (7 in the placebo group, 3 in the amifampridine group) who were taking amifampridine prior to enrollment.
1.Primary Outcome
Title Change From Baseline Quantitative Myasthenia Gravis (QMG) at 14 Days
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Amifampridine Phosphate
Hide 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).

Overall Number of Participants Analyzed 21 16
Mean (Standard Deviation)
Unit of Measure: QMG Score
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)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Amifampridine Phosphate
Comments [Not Specified]
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 [Not Specified]
Method Mixed Models Analysis
Comments Pairwise contrast at Day 14 from MMRM model.
2.Primary Outcome
Title Change in SGI Score
Hide 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.

  1. Terrible
  2. Mostly dissatisfied
  3. Mixed
  4. Partially satisfied
  5. Mostly satisfied
  6. Pleased
  7. Delighted
Time Frame Assessment at Baseline and Day 14
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title Placebo Amifampridine Phosphate
Hide 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).

Overall Number of Participants Analyzed 21 16
Mean (Standard Deviation)
Unit of Measure: SGI score
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)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.0028
Comments Pairwise contrast at Day 14 from MMRM model.
Method Mixed Models Analysis
Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline Timed 25 Foot Walking Test (T25FW) at 14 Days
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Amifampridine Phosphate
Hide 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).

Overall Number of Participants Analyzed 21 16
Mean (Standard Deviation)
Unit of Measure: feet/minute
Baseline 255  (111) 254  (126)
Day 14 244  (116) 253  (126)
Change from Baseline -10.4  (53.1) -1.46  (52.5)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.6274
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
4.Secondary Outcome
Title Change in CGI-I Score
Hide 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.

  1. = Very much improved
  2. = Much improved
  3. = Minimally improved
  4. = No change
  5. = Minimally worse
  6. = Much worse
  7. = Very much worse
Time Frame Baseline and Day 14
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Amifampridine Phosphate
Hide 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).

Overall Number of Participants Analyzed 21 16
Mean (Standard Deviation)
Unit of Measure: CGI-I score
Baseline 2.5  (0.98) 2.6  (0.63)
Day 14 4.8  (1.45) 3.6  (1.50)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.0267
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
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
Hide 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 (%) Affected / at Risk (%)
Total   0/22 (0.00%)   0/16 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Part 2 and Part 3 Placebo Part 2 and Part 3 Amifampridine Phosphate
Affected / at Risk (%) Affected / at Risk (%)
Total   0/22 (0.00%)   0/16 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Part 2 and Part 3 Placebo Part 2 and Part 3 Amifampridine Phosphate
Affected / at Risk (%) Affected / at Risk (%)
Total   6/21 (28.57%)   3/16 (18.75%) 
General disorders     
Asthenia  1  2/21 (9.52%)  0/16 (0.00%) 
Fatigue  1  1/21 (4.76%)  1/16 (6.25%) 
Infections and infestations     
Nasopharyngitis  1  0/21 (0.00%)  1/16 (6.25%) 
Otitis externa  1  0/21 (0.00%)  1/16 (6.25%) 
Periodontitis  1  1/21 (4.76%)  0/16 (0.00%) 
Pulpitis dental  1  1/21 (4.76%)  0/16 (0.00%) 
Urinary tract infection  1  0/21 (0.00%)  1/16 (6.25%) 
Investigations     
Blood creatine phosphokinase increased  1  1/21 (4.76%)  0/16 (0.00%) 
Musculoskeletal and connective tissue disorders     
Muscular weakness  1  1/21 (4.76%)  0/16 (0.00%) 
Sensation of heaviness  1  1/21 (4.76%)  0/16 (0.00%) 
Psychiatric disorders     
Depression  1  1/21 (4.76%)  0/16 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Dyspnoea  1  1/21 (4.76%)  0/16 (0.00%) 
1
Term from vocabulary, MedDRA 13.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Gary Ingenito
Organization: Catalyst Pharmaceuticals, Inc.
Phone: 305-420-3200
Responsible Party: Catalyst Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01377922     History of Changes
Other Study ID Numbers: LMS-002
First Submitted: June 17, 2011
First Posted: June 22, 2011
Results First Submitted: September 28, 2017
Results First Posted: January 4, 2018
Last Update Posted: January 4, 2018