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

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.

Study Overview

• Status: Completed
• Conditions: Lambert-Eaton Myasthenic Syndrome
• Intervention / Treatment: Drug: Placebo Oral Tablet; Drug: Amifampridine Phosphate

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 3

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female ≥18 years of age and currently receiving amifampridine phosphate for LEMS.
2. Diagnosis of LEMS by antibody testing or electromyography (EMG).
3. Completion of anti-cancer treatment at least 3 months (90 days) prior to Screening.
4. If receiving peripherally acting cholinesterase inhibitors (e.g. pyridostigmine), a stable dose of cholinesterase inhibitors is required for at least 7 days prior to randomization and throughout the study.
5. If receiving permitted oral immunosuppressants (prednisone or other corticosteroid), a stable dose is required for at least 30 days prior to randomization and throughout the study.
6. Female patients of childbearing potential must practice an effective, reliable contraceptive regimen during the study.
7. Able to perform all study procedures and assessments.
8. Willing and able to travel to study site and attend all clinic study visits.
9. Willing and able to provide written informed consent.

Exclusion Criteria:

1. Clinically significant long corrected QT (QTc) interval on ECG in previous 12 months.
2. Seizure disorder.
3. Active brain metastases.
4. Unable to ambulate.
5. Pregnant or lactating females.
6. Any other condition which, in the opinion of the Investigator, might interfere with the patient's participation in the study or confound the assessment of the patient.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: amifampridine phosphate; amifampridine phosphate 10 mg (amifampridine equivalent) by mouth, 30 to 80 mg total daily dose, 3 to 4 times per day for 4 days	Drug: Amifampridine Phosphate
Placebo Comparator: placebo (for amifampridine phosphate); placebo by mouth 3 to 4 times per day for 4 days	Drug: Placebo Oral Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitative Myasthenia Gravis (QMG) Score	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.	change from baseline in QMG score at end of day 4
Subject Global Impression (SGI) Score	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.	change from baseline in SGI score at end of day 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Clinician's Global Impression of Improvement (CGI-I) at Day 4 Compared to Baseline	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.	change from baseline in CGI-I score at end of day 4

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Triple Timed Up and Go Walk Test (3TUG)	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.	change from baseline in 3TUG at end of day 4

Collaborators and Investigators

• Sponsor: Catalyst Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Perry Shieh, MD, PhD, University of California, Los Angeles

Study record dates

Study Major Dates

• Study Start: November 1, 2016
• Primary Completion (Actual): October 1, 2017
• Study Completion (Actual): October 1, 2017

Study Registration Dates

• First Submitted: November 16, 2016
• First Submitted That Met QC Criteria: November 17, 2016
• First Posted (Estimate): November 21, 2016

Study Record Updates

• Last Update Posted (Actual): December 24, 2018
• Last Update Submitted That Met QC Criteria: December 20, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: LEMS
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Neoplasms; Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Neoplasms by Site; Disease; Neuromuscular Diseases; Neurodegenerative Diseases; Nervous System Neoplasms; Paraneoplastic Syndromes, Nervous System; Paraneoplastic Syndromes; Neuromuscular Junction Diseases; Myasthenia Gravis; Syndrome; Lambert-Eaton Myasthenic Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Membrane Transport Modulators; Neuromuscular Agents; Potassium Channel Blockers; Amifampridine
• Other Study ID Numbers: LMS-003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No