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Tyrosine

tablets equivalent to 10mg amifampridine, 3 to 4 times per day. Initially, the daily amifampridine doses were to be the doses that were determined at the end of the Run-in Period from the MSK-002 study. The usual range was from 30 to 80 mg total daily dose, given in three (3) or four (4) doses, with no single dose \> 20 mg

tablets equivalent to 10mg amifampridine, titrated to an efficacious and tolerable dose, 3 to 4 times a day

Amifampridine Phosphate

Renato Mantegazza, MD

Evaluate the long-term safety of amifampridine phosphate in patients with MuSK antibody positive and AChR antibody positive myasthenia gravis.

The Primary objective :

To characterize the long-term safety and tolerability of amifampridine phosphate in patients with MG

The Secondary Objective:

To assess the clinical efficacy of amifampridine phosphate over time in patients with MG based on change in Myasthenia Gravis Activities of Daily Living Score (MG-ADL)

This was a long-term extension study for subjects who participated in Protocol MSK-002 where the efficacy and safety of amifampridine was evaluated in subjects diagnosed with MuSK MG or AChR-MG. The optimal dose and schedule for amifampridine from the end of the Run-in Period from Study MSK-002 was initially used for each patient. The Investigator could adjust the dose of amifampridine during the course of the trial, in order to optimize neuromuscular benefit for the patient. Clinic visits for safety assessment and for evaluation of MG-ADL were made at Months 3, 6, 9, 12, 15, 21, 27, 33 and 39. Additional visits could occur at the discretion of the Investigator.

The Original protocol (12 Nov 2017) included analysis of MG-ADL change over time, however, Statistical Analysis Plan (SAP), dated 21 Feb 2023, removed the analysis of MG-ADL score change over time.

Long Term Safety Study of Amifampridine Phosphate in MuSK-MG (Muscle Specific Tyrosine Kinase Myasthenia Gravis)

Long Term Safety Study of Amifampridine Phosphate in Patients With MuSK Antibody Positive and AChR (Acetylcholine Receptor) Antibody Positive Myasthenia Gravis

Evaluate the long-term safety and tolerability of amifampridine phosphate through the number of patients with treatment-emergent adverse events mapped to the Medical Dictionary for Regulatory Activities (MedDRA) SOCs and PTs. \[ Time Frame: over 39 months \] Descriptive statistics will be used to summarize study data.

Catalyst Pharmaceuticals, Inc.

Serious classification based on the FDA regulatory definition of a serious AE.

Amifampridine Phosphate: tablets equivalent to 10mg amifampridine, titrated to an efficacious and tolerable dose, 3 to 4 times a day.

Serious Adverse Event

tablets equivalent to 10mg amifampridine, 3 to 4 times per day. Initially, the daily amifampridine doses were to be the doses that were determined at the end of the Run-in Period from the MSK-002 study. The usual range was from 30 to 80 mg total daily dose, given in three (3) or four (4) doses, with no single dose \> 20 mg

Amifampridine Phosphate: tablets equivalent to 10mg amifampridine, titrated to an efficacious and tolerable dose, 3 to 4 times a day

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Italy

Region of Enrollment

Baseline weight not recorded for 4 participants.

Weight

The study was terminated due to lack of measure appropriate data. The analysis of the MG-ADL score was removed in Statistical Analysis Plan (SAP), dated 21FEB2023.

Gary Ingenito, MD, Chief Medical Officer

Treatment Emergent Adverse Events

Number of Participants With Treatment-Emergent Adverse Events (Safety and Tolerability)

Overall Study

Diseases and Abnormalities at or Before Birth

Lambert-Eaton Myasthenic Syndrome

Myasthenic Syndromes, Congenital

Genetic Diseases, Inborn

Lambert Eaton Myasthenic Syndrome

Congenital Myasthenic Syndromes

Each patient will participate in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate is achieved for 7 days. After this phase, half of the subjects will be randomized to receive amifampridine in Period I and then crossed over to receive placebo in Period II. Each randomized treatment period is 7 days in duration and is separated by a re-stabilization period of approximately two weeks where the subject will be returned to the stable dose administered at the end of the open-label run-in period. Dosing will be between 20 - 80 mg per day and frequency will be between 2-4 times per day.

Each patient will participate in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate is achieved for 7 days. After this phase, half of the subjects will be randomized to receive placebo in Period I and then crossed over to receive amifampridine in Period II. Each randomized treatment period is 7 days in duration and separated by a re-stabilization period of approximately two weeks where the subject will be returned to the stable dose administered at the end of the open-label run-in period. Dosing will be between 20 - 80 mg per day and frequency will be between 2-4 times per day.

Amifampridine phosphate tablets 10 mg will be provided in round, white-scored tablets, and containing amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet.

amifampridine phosphate

A placebo equivalent will be provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo will be administered consistent with the dose regimen of amifampridine phosphate.

Placebo

Thomas Crawford, M.D.

This randomized, double-blind, controlled, outpatient two-period, two-treatment crossover study is designed to evaluate the efficacy and safety of amifampridine phosphate in patients (ages 2 and above) diagnosed with certain genetic subtypes of CMS and demonstrated open label (amifampridine phosphate) or history of sustained amifampridine benefit from treatment.

Each patient will participate in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate is achieved for 7 days. After this phase, blinded treatment effect will be assessed in a randomized fashion of continuation or cessation of drug (Placebo) starting with Period I (duration 7 days). Following experimental Period 1, patients will be returned to the stable dose administered at the end of the open-label run-in period for approximately 2 weeks, followed by cross over treatment in Period 2 dosing for 7 days. After completion of Period 2, patients will be eligible for expanded access with restoration of open-label amifampridine phosphate at the same dose and frequency as established in the run in phase of the study.

Amifampridine Phosphate for the Treatment of Congenital Myasthenic Syndromes

A Phase 3, Double-blind, Outpatient Crossover Study to Evaluate the Efficacy and Safety of Amifampridine Phosphate (3,4 Diaminopyridine Phosphate) in Patients With Congenital Myasthenic Syndromes (CMS)

Subject Global Impression (SGI) rates the subject's impression of the effects of the study medication during the preceding week with max score =7 (most satisfied) and min score =1 (least satisfied). It will be completed at D0 (baseline for Study Period 1), D8, D21 (baseline for Study Period 2), and D29. Change from baseline (CFB) will be assessed for Study Period 1 (difference in SGI score from D0 to D8), Study Period 2 (difference in SGI score from D21 to D29) and the change in CFB from Study Period 1 to Study Period 2 (difference between CFB during Study Period 1 and CFB during Study Period 2). A Mann-Whitney-Wilcoxon test for equality of the CFB results in the two treatments in Period 1 and for the equality of the CFB results in the two treatment sequences will be conducted. A mixed effects liner model will be fit with the SGI raw scores as a response and study arm, treatment, period, age group and mutation type as fixed effect terms and patient as a random effect.

Motor Function Measure 32 (MFM-32) evaluates the severity and progression of motor function in patients 7 years of age or older with max total score = 96 (best score) and min total score =0 (worst score). It will be completed at D0 (baseline for Study Period 1), D8, D21 (baseline for Study Period 2) and D29. CFB will be assessed for Study Period 1 (difference in MFM-32 from D0 to D8), Study Period 2 (difference in MFM-32 from D21 to D28) and the change in CFB from Study Period 1 to Study Period 2 (difference between CFB during Study Period 1 and CFB during Study Period 2). A Mann-Whitney-Wilcoxon test for equality of CFB results in the two treatments in Period 1 and for the equality of the CFB results in the two treatment sequences will be conducted. A mixed effects linear model will be fit to the overall MFM-32 score as the response variable and fixed effect terms for treatment, period, age group, genetic mutation type, and sequence\*period and a random effect for patient.

Motor Function Measure 20 (MFM-20) evaluates the severity and progression of motor function in patients 2 to 6 years of age with max total score = 60 (best score) and min total score =0 (worst score). It will be completed at D0 (baseline for Study Period 1), D8, D21 (baseline for Study Period 2) and D29. CFB will be assessed for Study Period 1 (difference in MFM-20 from D0 to D8), Study Period 2 (difference in MFM-20 from D21 to D28) and the change in CFB from Study Period 1 to Study Period 2 (difference between CFB during Study Period 1 and CFB during Study Period 2). A Mann-Whitney-Wilcoxon test for equality of CFB results in the two treatments in Period 1 and for the equality of the CFB results in the two treatment sequences will be conducted. A mixed effects linear model will be fit to the overall MFM-32 score as the response variable and fixed effect terms for treatment, period, age group, genetic mutation type, and sequence\*period and a random effect for patient.

Treatment administered to the patient at the time of onset of the AE. Includes patients who received amifampridine phosphate during the run-in period who were not randomized for inclusion in the crossover portion of the study.

Treatment administered to the patient at the time of onset of the AE.

Each patient will participate in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate is achieved for 7 days. After this phase, half of the subjects will be randomized to receive amifampridine in Period I and then crossed over to receive placebo in Period II. Each randomized treatment period is 7 days in duration and is separated by a re-stabilization period of approximately two weeks where the subject will be returned to the stable dose administered at the end of the open-label run-in period. Dosing will be between 20 - 80 mg per day and frequency will be between 2-4 times per day.

Amifampridine Phosphate: Amifampridine phosphate tablets 10 mg will be provided in round, white-scored tablets, and containing amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet.

Placebo: A placebo equivalent will be provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo will be administered consistent with the dose regimen of amifampridine phosphate.

Amifampridine Phosphate - Placebo

Each patient will participate in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate is achieved for 7 days. After this phase, half of the subjects will be randomized to receive placebo in Period I and then crossed over to receive amifampridine in Period II. Each randomized treatment period is 7 days in duration and separated by a re-stabilization period of approximately two weeks where the subject will be returned to the stable dose administered at the end of the open-label run-in period. Dosing will be between 20 - 80 mg per day and frequency will be between 2-4 times per day.

amifampridine phosphate: Amifampridine phosphate tablets 10 mg will be provided in round, white-scored tablets, and containing amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet.

Placebo: A placebo equivalent will be provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo will be administered consistent with the dose regimen of amifampridine phosphate.

Placebo - Amifampridine Phosphate

Total

Ethnicity (NIH/OMB)

Safety population: All randomized patients who have received at least one dose of study medication. Note that subjects in the Amifampridine Phosphate Only arm are excluded from this analysis, as they were not randomized for inclusion in the crossover portion of the study.

Gary Ingenito

A Mann-Whitney-Wilcoxon test for equality of the change from baseline (CFB) in the two treatments in Period 1 will be presented.

A mixed effects linear model will be fit to the data with SGI raw scores as the response and fixed effect terms for treatment, period, age group, mutation type and sequence\*period, and a random effect for patient. The LSMeans for the estimated difference between treatments in Period 1 along with a 95% confidence interval for this difference.

Study Period 1: CFB in SGI Score at Day 8

Study Period 2 : CFB in SGI Score at Day 29

The Full Analysis Set consists of all randomized patients who receive at least one dose of study medication and have at least one post-treatment efficacy assessment.

Subject Global Impression (SGI) Score Summary: Mann-Whitney Main Effects Test Results; SGI Score Mixed Model Analysis

A mixed effects linear model will be fit to the data with Overall MFM-32 scores as the response and fixed effect terms for treatment, period, age group, mutation type and sequence\*period, and a random effect for patient. The LSMeans for the estimated difference between treatments in Period 1 along with a 95% confidence interval for this difference.

Study Period 1: CFB in Overall MFM-32 Score at Day 8

Study Period 2: CFB in Overall MFM-32 Score at Day 29

Motor Function Measure 32 (MFM-32) Score Summary: Mann-Whitney Main Effect Test Results, MFM-32 Score Mixed Model Analysis

A mixed effects linear model will be fit to the data with Overall MFM-20 scores as the response and fixed effect terms for treatment, period, age group, mutation type and sequence\*period, and a random effect for patient. The LSMeans for the estimated difference between treatments in Period 1 along with a 95% confidence interval for this difference.

Study Period 1: CFB in Overall MFM-20 Score at Day 8

Study Period 2: CFB in Overall MFM-20 Score at Day 29

Motor Function Measure 20 (MFM-20) Score Mixed Model Analysis, MFM-20 Score Mixed Model Analysis

Patients receiving amifampridine during the open-label run-in period but were not randomized for the crossover portion of the study.

Amifampridine Phosphate Only

Matching placebo tablets administered 3-4 times a day (to the individual patient's tablet count of active at baseline) over 2 weeks.

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.

Charles W Gorodetzky, MD, PhD

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

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.

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

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)

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.

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

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.

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

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.

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.

Part 2 and Part 3 Placebo

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).

Part 2 and Part 3 Amifampridine Phosphate

Was the patient taking amifampridine (base or phosphate) immediately prior to enrollment?

Data only for those subjects (7 in the placebo group, 3 in the amifampridine group) who were taking amifampridine prior to enrollment.

If yes, number of continuous days of amifampridine exposure immediately prior to enrollment

Baseline

Day 14

Change from Baseline

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.

Change From Baseline Quantitative Myasthenia Gravis (QMG) at 14 Days

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

Change in SGI Score

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.

Change From Baseline Timed 25 Foot Walking Test (T25FW) at 14 Days

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

Change in CGI-I Score

Eye Diseases

Nystagmus, Pathologic

Dosage form: tablets containing the equivalent of 10 mg amifampridine per tablet.

Amifampridine Phosphate given based on Investigator assessment of optimal neuromuscular benefit. In adult patients \> 16 years of age, Doses ranged from 30 mg to 80 mg, divided into doses taken 3 to 4 times per day and in pediatric patients age \< 16 years the maximum daily dose was 60 mg/day. No single dose to exceed 20 mg.

Perry Shieh, MD, PhD

Primary:

The primary objective of this study under the original protocol was to provide neuromuscular specialists and neurologists access to amifampridine phosphate therapy for their patients with LEMS, CMS or downbeat nystagmus until the product became commercially available.

Secondary:

The secondary objective of this study under the original protocol was to provide additional long-term safety data on amifampridine phosphate in patients.

Primary The primary objective of this study after its fifth amendment was to provide access to amifampridine phosphate therapy to pediatric patients with LEMS, and pediatric and adult patients with CMS until the product became commercially available for these indications or development of the product for the indication was terminated.

Secondary:

The secondary objective of this study after its fifth amendment was to assess the long-term safety of amifampridine phosphate in pediatric patients with LEMS, and pediatric and adult patients with CMS.

This multicenter, expanded access study was designed to allow EAP-001 Investigators, neuromuscular specialists, and neurologists access to amifampridine phosphate therapy for their patients with LEMS, CMS, or downbeat nystagmus until such time the product became commercially available for these specific indications or development of the product for the indication was terminated. Given that these are chronic conditions, this study obtained some long-term safety data by evaluating Adverse Events, physical exams, vital signs, standard safety laboratory tests (chemistry, hematology, and urinalysis), pregnancy testing (if applicable) and abnormal ECG findings, where each of these data/measures were performed as part of a routine standard of care treatment provided by the Principal Investigator or the patient's personal physician(s) (i.e., could be performed by a different physician not involved in the treatment of neuromuscular disease).

Planned -100 sites in US and up to 200 patients. Actual- 50 sites activated and 200 patients enrolled.

Patients were seen at screening/baseline, Day 1 and at least once per year at the PIs discretion. With the COVID-19 Pandemic, telehealth visits were allowed and assessments that could be completed via remote telehealth visits were performed via phone or videoconference. Follow-up visits included Physical exams, vital signs, standard safety laboratory tests (chemistry, hematology, and urinalysis), pregnancy testing (if applicable) and ECGs.

Patients were titrated to an optimal individualized dose of amifampridine phosphate based on Principal Investigator assessment of optimal neuromuscular benefit. In patients already taking amifampridine base, amifampridine phosphate was started at an equivalent or lower dose of amifampridine phosphate, at the Principal Investigator's discretion. Therapeutic doses were to range from 10 to 80 mg, divided into doses taken two (2) to four (4) times per day, with a maximum single dose of 20 mg. For upward titration, amifampridine phosphate could be increased by 10 mg increments every four (4) to five (5) days to a maximum of 80 mg per day (ages \>16 years), and to a maximum of 60 mg (ages 2 to 16 years) based on optimal neuromuscular benefit and at the discretion of the Principal Investigator. If needed, titration could occur in 5 mg/dose and per day increments. Drug was shipped to the clinic for the first dose ( Day 1) and subsequent shipments were sent to the patients home by a specialty pharmacy.

In addition to amifampridine phosphate, patients received best supportive care (BSC) treatment as determined by the Principal Investigator using concomitant medications permitted by protocol, including selected oral immunosuppressant's (i.e., prednisone or other corticosteroids, azathioprine, mycophenolate) and peripherally acting cholinesterase inhibitors (e.g., pyridostigmine). Changes to BSC could be made at the Principal Investigator's discretion, as long as prohibited concomitant medications were not used.

Firdapse® was approved for adult patients with LEMS in November 2018 and approved for pediatric patients with LEMS ages 6 years and older in September 2022. The indications for CMS and DBN were not pursued.

Expanded Access Study Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS),Congenital Myasthenic Syndrome

An Open-Label, Expanded Access Protocol for Firdapse® (Amifampridine Phosphate; 3,4-Diaminopyridine Phosphate) Treatment in Pediatric Patients With Lambert-Eaton Myasthenic Syndrome (LEMS), and in Pediatric and Adult Patients With Congenital Myasthenic Syndromes (CMSs)

amifampridine phosphate 10 mg (amifampridine equivalent) by mouth, 30 to 80 mg total daily dose, 3 to 4 times per day for 4 days

placebo by mouth 3 to 4 times per day for 4 days

Placebo Oral Tablet

This study evaluates the effect of withdrawing amifampridine phosphate treatment from patients with LEMS. One half of the patients will continue to receive amifampridine phosphate and the other half will receive placebo, during this double-blind study.

This was a randomized (1:1), double-blind, placebo-controlled, parallel-group, withdrawal study designed to evaluate the efficacy and safety of amifampridine phosphate in patients diagnosed with LEMS. The study was planned to include approximately 28 male and female patients.

Prior to the study, patients were receiving unblinded treatment in the expanded access program (EAP-001). Patients had to be on a stable dose and frequency of amifampridine phosphate for at least 1 week prior to randomization into LMS-003. Screening and randomization (Day 0) may have been into a single visit.

Patients who met eligibility criteria were randomized 1:1 to amifampridine phosphate (at the patient's optimal dose) or placebo on Day 0.

Baseline assessments were obtained on Study Day 0, while the patient has been on open-label amifampridine phosphate and in relationship to the usual dosing schedule. Patients took blinded study medication on Day 1 through Day 3. On Day 4, a dose of blinded study medication was administered by the site study personnel. This was the same medication that the patient took on Day 1 through Day 3. The assessments listed below were performed following either the second, third, or fourth dose of medication taken on Day 4, and this should be the same dose after which Day 0 assessments were performed. For example, if the patient took their second dose of amifampridine in the clinic on Day 0 and had assessments started 40 minutes later, then on Day 4, that patient should be assessed after taking their second dose of investigational product (IP).

Beginning with the next dose after all Day 0 baseline assessments were completed, the patient received IP through Day 4, with a clinic visit on the last day (Day 4) for assessments.

The planned duration of participation for each patient was up to 12 days, including screening (up to 7 days), Day 0 assessments and randomization, and IP administration (Day 1 through Day 4).

Phase 3 Study to Evaluate Efficacy of Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS)

A Phase 3, Double-Blind, Placebo-controlled, Randomized, Parallel-Group Study to Evaluate the Efficacy and Safety of Amifampridine Phosphate in Patients With Lambert-Eaton Myasthenic Syndrome

The 3TUG is a functional mobility test that requires a patient to stand up from a straight-backed armchair, walk 3 meters, turn around, walk back, and sit down in the chair. A modification of this is where the individual performs the test 3 times without pause, and the measurement is the average time required to complete each of the 3 repetitions. Based upon literature reports that a significant change in gait for a similar walk-test is an increase in time of more than 20%, this has been incorporated into the endpoint.

The QMG is a physician-rated test including 13 assessments such as facial strength, swallowing, grip strength, and duration of time that limbs can be maintained in outstretched positions. Each assessment is graded as 0 (none), 1 (mild), 2 (moderate), or 3 (severe), for a total range of 0-39. A higher total score indicates a worse outcome.

The SGI is a 7-point scale on which the patient rates their global impression of the effects of a study treatment (1=terrible to 7=delighted). The SGI was assessed by the patient or the patient's parent/guardian/caregiver if the patient was unable to complete the SGI. The SGI has demonstrated concordance with the physician's assessment of improvement.

The CGI-I captures the Investigator's global impression of the patient's improvement or worsening from baseline status. The 7-point scale is scored by the Investigator based on changes in symptoms, behavior, and functional abilities. Each symptom is rated as 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), or 7 (very much worse). The total score can range from 0 to 49. A higher score indicates a worse outcome.

Treatment-emergent AEs (TEAEs) were summarized using system organ class and PT by treatment and overall for all patients in the safety population.

amifampridine phosphate 10 mg (amifampridine equivalent) by mouth, 30 to 80 mg total daily dose, 3 to 4 times per day for 4 days

Amifampridine Phosphate

placebo by mouth 3 to 4 times per day for 4 days

Placebo Oral Tablet

Placebo (for Amifampridine Phosphate)

Day 4

Change from baseline

Quantitative Myasthenia Gravis (QMG) Score

Change from baseline to Day 4

Subject Global Impression (SGI) Score

Change in Clinician's Global Impression of Improvement (CGI-I) at Day 4 Compared to Baseline

The number and proportion of patients with a ≥20% increase in 3TUG average time

Triple Timed Up and Go Walk Test (3TUG)

tablets matching amifampridine phosphate, 3 to 4 times a day

Efficacy and safety of amifampridine phosphate in improving the activities of daily living for patients with antibody positive MuSK myasthenia gravis.

Randomized, double-blind, placebo-controlled, parallel group study is designed to evaluate the safety, tolerability and efficacy of amifampridine phosphate in patients with MuSK-MG. In addition, a sample of AChR-MG patients will be assess for efficacy and safety of amifampridine phosphate. Planned duration of participation for each patient is at least 38 days, excluding the screening period. Eligible patients will be titrated to an efficacious dose of amifampridine phosphate and those who demonstrate improvement will be randomized to either placebo or amifampridine, in a double-blind fashion, for 10 days.

Study to Evaluate Amifampridine Phosphate in Patients With MuSK-MG

A Randomized, Placebo-control, Parallel Group Study to Evaluate the Effect of Amifampridine Phosphate in Patients With MuSK Antibody Positive Myasthenia Gravis, and a Sample of AChR Antibody Positive Myasthenia Gravis Patients

Myasthenia Gravis-Activities of Daily Living (MG-ADL) is a self-report scale to assess the patient's MG symptoms and functional performance of activities of daily living. The eight items are scored on a scale of 0-3 with 3 representing the most severe symptoms or impaired performance and 0 representing no symptoms or impaired performance. Each item was assessed by the patient at the last day (Day 0) of the Run-in period and at the post-treatment visit. The post-treatment result will be the result obtained on Day 10. If the patient discontinued treatment early, the post-treatment result may be obtained at an earlier time point. The total MG-ADL score was calculated as the sum of each item score, with a maximum score of 24 (most severe symptoms/impairment) and minimum score of 0 (least severe symptoms/impairment). The change from baseline (CFB) at Day 10 was assessed. A Wilcoxon-Mann-Whitney Rank Sum Test of equality of change from baseline distributions between subjects diagnos

Quantitative Myasthenia Gravis (QMG) assesses the patient's general body strength and fatigability. Each test item is scored on a scale of 0-3 with 3 representing the most severe symptom results and 0 representing no symptom results. Each item was assessed by the patient at Screening, the first (Day 1) and last day (Day 0) of the Run-in period and at the post-treatment visit. The post-treatment result will be the result obtained on Day 10. If the patient discontinued treatment early, the post-treatment result may be obtained at an earlier time point. The total QMG score was calculated as the sum of each item score, with a maximum score of 39 (most severe symptoms) and minimum score of 0 (least severe symptoms). The change from baseline (CFB) at Day 10 was assessed. A Wilcoxon-Mann-Whitney Rank Sum Test of equality of change from baseline distributions between subjects diagnosed with MuSK-MG treated with amifampridine and placebo was conducted.

Amifampridine Phosphate: tablets equivalent to 10mg amifampridine, titrated to an efficacious and tolerable dose, 3 to 4 times a day.

The AEs reported within this treatment arm are those experienced by all participants who received Amifampridine Phosphate at the time of onset of the AE. Because this study has a run-in period where all subjects received Amifampridine Phosphate, the number of at-risk subjects in this treatment arm is identical to the overall number of at-risk participants. That is, the at-risk count includes those randomized to the Amifampridine Phosphate-Placebo sequence, Placebo - Amifampridine Phosphate sequence and those that received Amifampridine Phosphate during the open-label Run-in period but were not randomized for the crossover portion of the study.

Placebo Oral Tablet: tablets matching amifampridine phosphate, 3 to 4 times a day

The AEs reported within this treatment arm are those experienced by participants who received Placebo at the time of onset of the AE. This includes those randomized to the Placebo - Amifampridine Phosphate sequence.

Includes all participants who received study drug, including Amifampridine Phosphate during the open-label Run-in period or double-blind treatment period or Placebo during the double-blind treatment period.

Overall

Amifampridine Phosphate: tablets equivalent to 10mg amifampridine, titrated to an efficacious and tolerable dose, 3 to 4 times a day

Placebo Oral Tablet: tablets matching amifampridine phosphate, 3 to 4 times a day

Patients receiving Amifampridine during the open-label Run-in period but were not randomized for the crossover portion of the study.

Height

The analysis of baseline characteristics included all patients in the Safety population, who are those patients who enrolled and received at least one dose of amifampridine. Patients who began the run-in period belong to the Safety population whether they were randomized to treatment or not.

A Wilcoxon-Mann-Whitney Rank Sum Test of equality of change from baseline distributions between subjects diagnosed with MuSK-MG treated with amifampridine and placebo was conducted.

Baseline (Day 0) MG-ADL Total Raw Score

Post-Baseline(Day 10 or time at which a patient discontinued treatment) MG-ADL Total Raw Score

CFB MG-ADL Total Score

Amifampridine Phosphate: tablets equivalent to 10mg amifampridine, titrated to an efficacious and tolerable dose, 3 to 4 times a day

Patients randomized to receive Amifampridine and diagnosed with MuSK-MG.

Amifampridine Phosphate - MuSK

Placebo Oral Tablet: tablets matching amifampridine phosphate, 3 to 4 times a day

Patients randomized to receive Placebo and diagnosed with MuSK-MG.

Placebo - MuSK

Amifampridine Phosphate: tablets equivalent to 10mg amifampridine, titrated to an efficacious and tolerable dose, 3 to 4 times a day

Patients randomized to receive Amifampridine and diagnosed with AChR-MG.

Amifampridine Phosphate - AChR

Placebo Oral Tablet: tablets matching amifampridine phosphate, 3 to 4 times a day

Patients randomized to receive Placebo and diagnosed with AChR-MG.

Placebo - AChR

The analysis of primary outcome data was based on the Full Analysis Set population, which included all randomized patients who received at least one dose of study medication (amifampridine or placebo post randomization) and had at least one post-treatment efficacy assessment. Patients who discontinued with no post-randomization data (no Day 0 and no Day 10 data) were excluded from all efficacy analyses but were included in the safety analyses.

Myasthenia Gravis-Activities of Daily Living (MG-ADL) Summary by Time Point and Myasthenia Gravis Type: Wilcoxon-Mann-Whitney Rank Sum Test Results

Baseline (Day 0) QMG Total Raw Score

Post-Baseline (day 10 or time at which a patient discontinued treatment early) QMG Total Raw Score

CFB QMG Total Score

The analysis of secondary outcome data was based on the Full Analysis Set population, which included all randomized patients who received at least one dose of study medication (amifampridine or placebo post randomization) and had at least one post-treatment efficacy assessment. Patients who discontinued with no post-randomization data (no Day 0 and no Day 10 data) were excluded from all efficacy analyses but were included in the safety analyses.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Long Term Safety Study of Amifampridine Phosphate in MuSK-MG (Muscle Specific Tyrosine Kinase Myasthenia Gravis)	NCT03579966	Myasthenia Grav... AChR Myasthenia...	Amifampridine P...	18 Years -	Catalyst Pharmaceuticals, Inc.
Amifampridine Phosphate for the Treatment of Congenital Myasthenic Syndromes	NCT02562066	Myasthenic Synd...	amifampridine p... Placebo	2 Years - 70 Years	Catalyst Pharmaceuticals, Inc.
A Phase 3 Study of Amifampridine Phosphate in Patients With Lambert Eaton Myasthenic Syndrome (LEMS)	NCT01377922	Lambert Eaton M...	Amifampridine P... Placebo	18 Years -	Catalyst Pharmaceuticals, Inc.
Expanded Access Study Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS),Congenital Myasthenic Syndrome	NCT02189720	Congenital Myas... Lambert-Eaton M... Nystagmus, Acqu...	Amifampridine P...	2 Years -	Catalyst Pharmaceuticals, Inc.
Expanded Access Study Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS),Congenital Myasthenic Syndrome	NCT02189720	Congenital Myas... Lambert-Eaton M... Nystagmus, Acqu...	Amifampridine P...	2 Years -	Catalyst Pharmaceuticals, Inc.
Phase 3 Study to Evaluate Efficacy of Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS)	NCT02970162	Lambert-Eaton M...	Amifampridine P... Placebo Oral Ta...	18 Years -	Catalyst Pharmaceuticals, Inc.
A Phase 3 Study of Amifampridine Phosphate in Patients With Lambert Eaton Myasthenic Syndrome (LEMS)	NCT01377922	Lambert Eaton M...	Amifampridine P... Placebo	18 Years -	Catalyst Pharmaceuticals, Inc.
Amifampridine Phosphate for the Treatment of Congenital Myasthenic Syndromes	NCT02562066	Myasthenic Synd...	amifampridine p... Placebo	2 Years - 70 Years	Catalyst Pharmaceuticals, Inc.
Phase 3 Study to Evaluate Efficacy of Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS)	NCT02970162	Lambert-Eaton M...	Amifampridine P... Placebo Oral Ta...	18 Years -	Catalyst Pharmaceuticals, Inc.
Study to Evaluate Amifampridine Phosphate in Patients With MuSK-MG	NCT03304054	Myasthenia Grav...	Amifampridine P... Placebo Oral Ta...	18 Years -	Catalyst Pharmaceuticals, Inc.

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