Controlled Trial to Evaluate Amifampridine Phosphate in Spinal Muscular Atrophy Type 3 Patients

Phase 2

Completed

Brief Summary: A two-period, two-treatment, crossover study to evaluate the safety, tolerability and efficacy of amifampridine phosphate in ambulatory patients diagnosed with spinal muscular atrophy (SMA) Type 3.

Detailed Description: This randomized (1:1), double-blind, placebo-controlled, 2-period, 2-treatment, crossover, outpatient study is designed to evaluate the safety, tolerability and efficacy of amifampridine phosphate in ambulatory patients diagnosed with SMA Type 3. The study is planned to include approximately 12 male and female SMA Type 3 patients. The planned duration of participation for each patient is approximately 2 months, based upon length of dose titration and excluding the screening period, which can last up to 14 days. Patients should only be taking the assigned investigational product (amifampridine phosphate 10 mg tablets or matching placebo tablets), no new therapies are permitted during the study.

Recruitment & Eligibility

Inclusion Criteria

Willing and able to provide written informed consent after the nature of the study has been explained and before the start of any research-related procedures.
Male or female between the ages of 6 and 50 years.
Genetically confirmed diagnosis of SMA Type 3.
Able to walk independently for at least 30 meters.
Not taking Nusinersen for the treatment of SMA (Nusinersen should be stopped at least 6 months before screening). Salbutamol is permitted only if the dose has been stable during the 6 months before screening.
Able to swallow oral medication.
Female patients of childbearing potential must have a negative pregnancy test (serum human chorionic gonadotropin [HCG] at Screening); and must practice an effective, reliable contraceptive regimen during the study and for up to 30 days following discontinuation of treatment.
Ability to participate in the study based on overall health of the patient and disease prognosis, as applicable, in the opinion of the Investigator; and able to comply with all requirements of the protocol, including completion of study questionnaires.

Exclusion Criteria

Epilepsy and currently on medication for epilepsy.
Concomitant use of medicinal products with a known potential to cause QTc prolongation.
Patients with long QT syndromes.
An electrocardiogram (ECG) within 6 months before starting treatment that shows clinically significant abnormalities, in the opinion of the Investigator.
Breastfeeding or pregnant at Screening or planning to become pregnant at any time during the study.
Treatment with an investigational drug (other than amifampridine), device, or biological agent within 6 months prior to Screening or while participating in this study.
Surgery for scoliosis or joint contractures within the previous 6 months.
Any medical condition that, in the opinion of the Investigator, might interfere with the patient's participation in the study, poses an added risk for the patient, or confound the assessment of the patient.
History of drug allergy to any pyridine-containing substances or any amifampridine excipient(s).
Less than a 3-point improvement in HFSME from start of the Open label Run -in period to end of Run-in (Day 0).

Arm && Interventions

Group	Intervention	Description
Placebo - Amifampridine Phosphate	Amifampridine Phosphate	Oral tablets, 30 to 80 mg per day in divided doses 3 to 4 times a day for 4 weeks
Amifampridine Phosphate - Placebo	Amifampridine Phosphate	Oral tablets, 30 to 80 mg per day in divided doses 3 to 4 times a day for 4 weeks
Placebo - Amifampridine Phosphate	Placebo Oral Tablet	Oral tablets, 30 to 80 mg per day in divided doses 3 to 4 times a day for 4 weeks
Amifampridine Phosphate - Placebo	Placebo Oral Tablet	Oral tablets, 30 to 80 mg per day in divided doses 3 to 4 times a day for 4 weeks

Primary Outcome Measures

Name	Time	Method
Hammersmith Functional Motor Scale Expanded (HFMSE) Summary Statistics and Mixed Model Analysis	Screening, the first (Day 1) and last day (Day 0) of the Run-in period, during Period 1 at Day 7 and Day 14, and during Period 2 at Day 21 and Day 28	Hammersmith Functional Motor Scale Expanded (HFMSE) assesses motor function by functional item in order of progressive difficulty, with higher values showing higher function abilities. Each item is scored on a scale of 0-2 with 2 representing item achieved unaided and 0 representing inability to achieve item. Each item was assessed by the patient at Screening, the first (Day 1) and last day (Day 0) of the Run-in period, during Period 1 at Day 7 and Day 14, and during Period 2 at Day 21 and Day 28. The total HFMSE score was calculated as the sum of each item score, with a maximum score of 66 (all items achieved unaided) and minimum score of 0 (all items failed). Change from baseline (CFB) will be assessed from Day 0 to Day 28. A mixed effects liner model was fit with the HFMSE change from baseline (CFB) scores at Day 28 as a response and treatment, sequence, and treatment by sequence as fixed effect terms and patient as a random effect.

Secondary Outcome Measures