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Amifampridine

Potassium Channel Blockers

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.

Catalyst Pharmaceuticals, Inc.

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.

Amifampridine Phosphate

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

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (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

Overall Study

Treatment use of 3,4-DAP for patients with congenital myasthenic syndrome (CMS)

3,4-diaminopyridine

Vern C. Juel, M.D.

This protocol has provided 3,4 diaminopyridine (DAP) under a treatment-use IND to patients with congenital myasthenic syndrome (CMS). It is currently closed to enrollment.

CMS diagnoses are made based on clinical, electromyographic and molecular genetic findings, and all patients have been referred to the PI for DAP treatment. This study enrolled minors and adults.

CMS patients under age 18 years were included if their parent or guardian gave written permission. Minors who turned 18 while in the program were re-consented as adults.

The dose of DAP is determined individually for each patient. Adults were started with a dose of 10 mg 3-4 times daily, increased over several weeks to the dose that produced the maximum symptomatic response, not to exceed 100 mg daily. Pyridostigmine bromide (PB) was often added at low doses and increased to the dose that produced the best response, not to exceed 360 mg daily. In children, equivalent doses of these medications was calculated on a surface area basis. The doses of DAP and PB are periodically adjusted to assure that the smallest effective doses are used.

Patients with significant clinical benefit from DAP, as judged by the study PI and the patient, may continue taking DAP as long as the drug is available from the sponsor, and as long as they return for regular follow-up evaluations at the Duke MG Clinic. Patients who are unable to return for regular follow-up will be required to obtain DAP from commercial or other compassionate sources via a physician actively managing their care.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Amifampridine Phosphate for the Treatment of Congenital Myasthenic Syndromes	NCT02562066	Myasthenic Synd...	amifampridine p... Placebo	2 Years - 70 Years	Catalyst Pharmaceuticals, Inc.
Treatment Use of 3,4-Diaminopyridine	NCT01765140	Myasthenic Synd...	3,4-diaminopyri...	-	Duke University
Treatment Use of 3,4-Diaminopyridine	NCT01765140	Myasthenic Synd...	3,4-diaminopyri...	-	Duke University
Amifampridine Phosphate for the Treatment of Congenital Myasthenic Syndromes	NCT02562066	Myasthenic Synd...	amifampridine p... Placebo	2 Years - 70 Years	Catalyst Pharmaceuticals, Inc.
Treatment Use of 3,4-Diaminopyridine	NCT01765140	Myasthenic Synd...	3,4-diaminopyri...	-	Duke University

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