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

• ClinicalTrials.gov Identifier: NCT02970162
• Recruitment Status: Completed
• First Posted: November 21, 2016
• Results First Posted: December 24, 2018
• Last Update Posted: December 24, 2018
• Sponsor: Catalyst Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Catalyst Pharmaceuticals, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Lambert-Eaton Myasthenic Syndrome	Drug: Amifampridine Phosphate; Drug: Placebo Oral Tablet	Phase 3

Expanded Access : An investigational treatment associated with this study is no longer available outside the clinical trial.   More info ...

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: November 2016
• Actual Primary Completion Date: October 2017
• Actual Study Completion Date: October 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Quantitative Myasthenia Gravis (QMG) Score [ Time Frame: change from baseline in QMG score at end of day 4 ]
   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.
2. Subject Global Impression (SGI) Score [ Time Frame: change from baseline in SGI score at end of day 4 ]
   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.

Secondary Outcome Measures :

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

Other Outcome Measures:

1. Triple Timed Up and Go Walk Test (3TUG) [ Time Frame: change from baseline in 3TUG at end of day 4 ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

UCLA

Los Angeles, California, United States, 90095

Sponsors and Collaborators

Catalyst Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Perry Shieh, MD, PhD; University of California, Los Angeles

  Study Documents (Full-Text)

Documents provided by Catalyst Pharmaceuticals, Inc.:

Study Protocol  [PDF] April 27, 2017

Statistical Analysis Plan  [PDF] July 12, 2017

More Information

• Responsible Party: Catalyst Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02970162
• Other Study ID Numbers: LMS-003
• First Posted: November 21, 2016
• Results First Posted: December 24, 2018
• Last Update Posted: December 24, 2018
• Last Verified: December 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Catalyst Pharmaceuticals, Inc.:

LEMS

Additional relevant MeSH terms:

Lambert-Eaton Myasthenic Syndrome; Syndrome; Disease; Pathologic Processes; Myasthenia Gravis; Paraneoplastic Syndromes, Nervous System; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Paraneoplastic Syndromes; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Neurodegenerative Diseases; Neuromuscular Junction Diseases; Neuromuscular Diseases; Autoimmune Diseases; Immune System Diseases; Amifampridine; Neuromuscular Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Potassium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action