Muscular Atrophy, Spinal
Conditions
Keywords
Type 3
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.
Interventions
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.
DRUGPlacebo Oral Tablet
Placebo Oral Tablet
Sponsors
Catalyst Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
1. 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. 2. Male or female between the ages of 6 and 50 years. 3. Genetically confirmed diagnosis of SMA Type 3. 4. Able to walk independently for at least 30 meters. 5. 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. 6. Able to swallow oral medication. 7. 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. 8. 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
1. Epilepsy and currently on medication for epilepsy. 2. Concomitant use of medicinal products with a known potential to cause QTc prolongation. 3. Patients with long QT syndromes. 4. An electrocardiogram (ECG) within 6 months before starting treatment that shows clinically significant abnormalities, in the opinion of the Investigator. 5. Breastfeeding or pregnant at Screening or planning to become pregnant at any time during the study. 6. Treatment with an investigational drug (other than amifampridine), device, or biological agent within 6 months prior to Screening or while participating in this study. 7. Surgery for scoliosis or joint contractures within the previous 6 months. 8. 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. 9. History of drug allergy to any pyridine-containing substances or any amifampridine excipient(s). 10. Less than a 3-point improvement in HFSME from start of the Open label Run -in period to end of Run-in (Day 0).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Italy
Participant flow
Recruitment details
The study was conducted from 14 January 2019 - 17 September 2020 at two sites in Europe.
Pre-assignment details
A screening visit was conducted to ensure that each patient met inclusion/exclusion criteria for the study. Those patients successfully completing screening had procedures/assessments conducted at the start of the Run-in period (Day 1, before starting study medication) and during Run-in, until stable dose and frequency of amifampridine was established for at least 7 days, and at least a 3-point improvement in HFMSE score was achieved from start of Run-in to be eligible for randomization (Day 0).
Participants by arm
| Arm | Count |
|---|---|
| Amifampridine Phosphate - Placebo Each patient participated in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate was achieved for 7 days. After this phase, half of the subjects were randomized to receive amifampridine in Period 1 and then crossed over to receive placebo in Period 2. Each randomized treatment period was 14 days in duration.
Dosing was up to 80 mg per day and frequency was between 3-4 times per day. Amifampridine Phosphate: Amifampridine phosphate tablets 10 mg were provided in round, white-scored tablets, and contained amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet.
Placebo: A placebo equivalent was provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo was administered consistent with the dose and dose regimen of amifampridine phosphate. | 6 |
| Placebo - Amifampridine Phosphate Each patient participated in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate was achieved for 7 days. After this phase, half of the subjects were randomized to receive placebo in Period 1 and then crossed over to receive amifampridine in Period 2. Each randomized treatment period was 14 days in duration.
Dosing was up to 80 mg per day and frequency was between 3-4 times per day. Placebo: A placebo equivalent was provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo was administered consistent with the dose and dose regimen of amifampridine phosphate.
Amifampridine Phosphate: Amifampridine phosphate tablets 10 mg were provided in round, white-scored tablets, and contained amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet. | 6 |
| Not Randomized Patients receiving amifampridine during the open-label run-in period but were not randomized to receive treatment. | 1 |
| Total | 13 |
Baseline characteristics
| Characteristic | Amifampridine Phosphate - Placebo | Placebo - Amifampridine Phosphate | Not Randomized | Total |
|---|---|---|---|---|
| Age, Continuous | 37.2 years STANDARD_DEVIATION 8.5 | 30.2 years STANDARD_DEVIATION 13.5 | 45.0 years | 34.5 years STANDARD_DEVIATION 11.3 |
| BMI | 22.5 kg/m^2 STANDARD_DEVIATION 1.4 | 22.3 kg/m^2 STANDARD_DEVIATION 4.3 | 26.6 kg/m^2 | 22.7 kg/m^2 STANDARD_DEVIATION 3.1 |
| Height | 169.3 cm STANDARD_DEVIATION 9 | 174.8 cm STANDARD_DEVIATION 6.1 | 170.0 cm | 171.9 cm STANDARD_DEVIATION 7.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 5 Participants | 1 Participants | 12 Participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 1 Participants | 8 Participants |
| Weight | 64.7 kg STANDARD_DEVIATION 9.3 | 67.8 kg STANDARD_DEVIATION 11.8 | 76.9 kg | 67.0 kg STANDARD_DEVIATION 10.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 5 / 12 | 3 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Hammersmith Functional Motor Scale Expanded (HFMSE) Summary Statistics and Mixed Model Analysis
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.
Time frame: 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
Population: The analysis of primary outcome data was based on the Full Analysis Set population, which included all randomized patients who received at least one dose of study medication (amifampridine or placebo) and had at least one post-treatment efficacy assessment. Patients are compared for efficacy according to the treatment to which they were randomized, regardless of the treatment actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Amifampridine Phosphate | Hammersmith Functional Motor Scale Expanded (HFMSE) Summary Statistics and Mixed Model Analysis | 0.208 Overall Score | Standard Error 0.326 |
| Placebo | Hammersmith Functional Motor Scale Expanded (HFMSE) Summary Statistics and Mixed Model Analysis | -0.583 Overall Score | Standard Error 0.326 |
Comparison: 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.p-value: 0.008395% CI: [0.22, 1.37]Mixed Models Analysis