Trial Outcomes & Findings for Amifampridine Phosphate for the Treatment of Congenital Myasthenic Syndromes (NCT NCT02562066)

NCT ID: NCT02562066

Last Updated: 2021-04-02

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

20 participants

Primary outcome timeframe

Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29

Results posted on

2021-04-02

Participant Flow

The study was conducted from 08 February 2016 - 24 January 2019 and was conducted at six sites in the United States and two sites in Canada, although one site (Montreal Neurological Institute and Hospital) did not enroll any patients.

Screening ensured patients met I/E criteria. Patients naïve to amifampridine began open-label titration until a stable dose and frequency was achieved for 7 days. Demonstrated efficacy (assessed by improvement on the MFM) was required to participate in the randomized portion of the study. Patients already on a stable dose with hostory of meaningful improvement were eligible immediately and transitioned to an equivalent dose of amifampridine phosphate for 7 days prior to randomization.

Participant milestones

Participant milestones
Measure	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 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.	Placebo - Amifampridine Phosphate 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.	Amifampridine Phosphate Only Patients receiving amifampridine during the open-label run-in period but were not randomized for the crossover portion of the study.
Overall Study STARTED	8	8	4
Overall Study COMPLETED	7	7	0
Overall Study NOT COMPLETED	1	1	4

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Amifampridine Phosphate for the Treatment of Congenital Myasthenic Syndromes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Amifampridine Phosphate - Placebo n=8 Participants 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.	Placebo - Amifampridine Phosphate n=8 Participants 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.	Total n=16 Participants Total of all reporting groups
Age, Categorical <=18 years	7 Participants n=99 Participants	5 Participants n=107 Participants	12 Participants n=206 Participants
Age, Categorical Between 18 and 65 years	1 Participants n=99 Participants	2 Participants n=107 Participants	3 Participants n=206 Participants
Age, Categorical >=65 years	0 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants
Age, Continuous	12.59 years STANDARD_DEVIATION 15.70 • n=99 Participants	27.35 years STANDARD_DEVIATION 25.00 • n=107 Participants	19.97 years STANDARD_DEVIATION 21.56 • n=206 Participants
Sex: Female, Male Female	5 Participants n=99 Participants	3 Participants n=107 Participants	8 Participants n=206 Participants
Sex: Female, Male Male	3 Participants n=99 Participants	5 Participants n=107 Participants	8 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	8 Participants n=99 Participants	7 Participants n=107 Participants	15 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Asian	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	0 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants
Race (NIH/OMB) White	8 Participants n=99 Participants	5 Participants n=107 Participants	13 Participants n=206 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	2 Participants n=107 Participants	2 Participants n=206 Participants

PRIMARY outcome

Timeframe: Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29

Population: 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.

Outcome measures

Outcome measures
Measure	Amifampridine Phosphate - Placebo n=8 Participants 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.	Placebo - Amifampridine Phosphate n=8 Participants 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.
Subject Global Impression (SGI) Score Summary: Mann-Whitney Main Effects Test Results; SGI Score Mixed Model Analysis Study Period 1: CFB in SGI Score at Day 8	-0.13 Scores on a scale Standard Deviation 1.81	-1.75 Scores on a scale Standard Deviation 2.12
Subject Global Impression (SGI) Score Summary: Mann-Whitney Main Effects Test Results; SGI Score Mixed Model Analysis Study Period 2 : CFB in SGI Score at Day 29	-0.75 Scores on a scale Standard Deviation 1.75	-1.14 Scores on a scale Standard Deviation 1.68

SECONDARY outcome

Timeframe: Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Amifampridine Phosphate - Placebo n=8 Participants 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.	Placebo - Amifampridine Phosphate n=8 Participants 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.
Motor Function Measure 32 (MFM-32) Score Summary: Mann-Whitney Main Effect Test Results, MFM-32 Score Mixed Model Analysis Study Period 1: CFB in Overall MFM-32 Score at Day 8	3.00 Score on a Scale Standard Deviation 3.92	-0.17 Score on a Scale Standard Deviation 4.58
Motor Function Measure 32 (MFM-32) Score Summary: Mann-Whitney Main Effect Test Results, MFM-32 Score Mixed Model Analysis Study Period 2: CFB in Overall MFM-32 Score at Day 29	0.75 Score on a Scale Standard Deviation 2.22	-0.60 Score on a Scale Standard Deviation 0.89

SECONDARY outcome

Timeframe: Study Period 1: Baseline (Day 0), Day 8; Study Period 2: Baseline (Day 21), Day 29

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Amifampridine Phosphate - Placebo n=8 Participants 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.	Placebo - Amifampridine Phosphate n=8 Participants 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.
Motor Function Measure 20 (MFM-20) Score Mixed Model Analysis, MFM-20 Score Mixed Model Analysis Study Period 1: CFB in Overall MFM-20 Score at Day 8	-1.50 Score on a Scale Standard Deviation 4.20	-0.50 Score on a Scale Standard Deviation 6.36
Motor Function Measure 20 (MFM-20) Score Mixed Model Analysis, MFM-20 Score Mixed Model Analysis Study Period 2: CFB in Overall MFM-20 Score at Day 29	-0.75 Score on a Scale Standard Deviation 0.50	1.50 Score on a Scale Standard Deviation 2.12

Adverse Events

Amifampridine Phosphate

Serious events: 1 serious events

Other events: 11 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Amifampridine Phosphate n=20 participants at risk 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.	Placebo n=20 participants at risk Treatment administered to the patient at the time of onset of the AE.
General disorders Pyrexia	0.00% 0/20 • Serious adverse events (SAEs) were recorded for each patient from the time informed consent was obtained and continues through four weeks after the last dose or at the early discontinuation visit, for a total of approximately 14 weeks. Non-serious AEs were recorded for each patient after informed consent is obtained and the first administration of study drug (on Day 1 of run-in) through the last visit or at the early discontinuation visit, for a total of approximately 10 weeks .	5.0% 1/20 • Serious adverse events (SAEs) were recorded for each patient from the time informed consent was obtained and continues through four weeks after the last dose or at the early discontinuation visit, for a total of approximately 14 weeks. Non-serious AEs were recorded for each patient after informed consent is obtained and the first administration of study drug (on Day 1 of run-in) through the last visit or at the early discontinuation visit, for a total of approximately 10 weeks .
Infections and infestations Parainfluenzae virus infection	0.00% 0/20 • Serious adverse events (SAEs) were recorded for each patient from the time informed consent was obtained and continues through four weeks after the last dose or at the early discontinuation visit, for a total of approximately 14 weeks. Non-serious AEs were recorded for each patient after informed consent is obtained and the first administration of study drug (on Day 1 of run-in) through the last visit or at the early discontinuation visit, for a total of approximately 10 weeks .	5.0% 1/20 • Serious adverse events (SAEs) were recorded for each patient from the time informed consent was obtained and continues through four weeks after the last dose or at the early discontinuation visit, for a total of approximately 14 weeks. Non-serious AEs were recorded for each patient after informed consent is obtained and the first administration of study drug (on Day 1 of run-in) through the last visit or at the early discontinuation visit, for a total of approximately 10 weeks .
Infections and infestations Rhinovirus infection	5.0% 1/20 • Serious adverse events (SAEs) were recorded for each patient from the time informed consent was obtained and continues through four weeks after the last dose or at the early discontinuation visit, for a total of approximately 14 weeks. Non-serious AEs were recorded for each patient after informed consent is obtained and the first administration of study drug (on Day 1 of run-in) through the last visit or at the early discontinuation visit, for a total of approximately 10 weeks .	0.00% 0/20 • Serious adverse events (SAEs) were recorded for each patient from the time informed consent was obtained and continues through four weeks after the last dose or at the early discontinuation visit, for a total of approximately 14 weeks. Non-serious AEs were recorded for each patient after informed consent is obtained and the first administration of study drug (on Day 1 of run-in) through the last visit or at the early discontinuation visit, for a total of approximately 10 weeks .
Vascular disorders Hypotension	0.00% 0/20 • Serious adverse events (SAEs) were recorded for each patient from the time informed consent was obtained and continues through four weeks after the last dose or at the early discontinuation visit, for a total of approximately 14 weeks. Non-serious AEs were recorded for each patient after informed consent is obtained and the first administration of study drug (on Day 1 of run-in) through the last visit or at the early discontinuation visit, for a total of approximately 10 weeks .	5.0% 1/20 • Serious adverse events (SAEs) were recorded for each patient from the time informed consent was obtained and continues through four weeks after the last dose or at the early discontinuation visit, for a total of approximately 14 weeks. Non-serious AEs were recorded for each patient after informed consent is obtained and the first administration of study drug (on Day 1 of run-in) through the last visit or at the early discontinuation visit, for a total of approximately 10 weeks .

Other adverse events

Additional Information

Gary Ingenito

Catalyst Pharmaceuticals, Inc.

Phone: 305-420-3200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place