Long Term Safety of Amifampridine Phosphate in Spinal Muscular Atrophy 3

This open-label outpatient extension study was designed to evaluate the long-term safety and tolerability of amifampridine in patients diagnosed with SMA Type 3. In addition, the evaluation of the effects of amifampridine on the QoL was performed. The study was planned to enroll those patients who had completed the SMA-001 study and after all final evaluations for that study had been completed, or those who demonstrated benefit after completing the dose titration period but failed to meet the randomization criteria on Day 0 of SMA-001.

The duration of participation for each patient was expected to be at least 12 months as patients could continue in the study until amifampridine was approved by Regulatory Agencies or the clinical development of amifampridine was terminated for this indication. In addition to amifampridine, patients continued to receive previous concomitant medications, as needed.

• Amifampridine Phosphate 10 MG Oral Tablet (Drug): Oral tablets

Primary outcomes

• Long-term Safety and Tolerability of Amifampridine [18 months]: Number of subjects with treatment emergent adverse events (TEAE).

Secondary outcomes

• To Assess the Clinical Efficacy of Amifampridine Phosphate Over Time in Patients With SMA Type 3 Based on Changes in Quality of Life (QoL). [Screening to end of study.]: Quality of life (QoL): the Individualized Quality of Life for neuromuscular disease (INQoL) or the Pediatric Quality of Life (PEDSQLTM) was used for adult or pediatric patients, respectively. Since there were no pediatric patients, none of the patients completed the PEDSQL. The INQol evaluated weakness, pain, fatigue, double vision, muscle locking, droopy eyelids, swallowing difficulties, activities, social relationships, emotions and body image. Each of these areas were measured in four categories as follows: 1- Incidence (0= No, 1 =Yes), 2-Severity (0= None to 7 = extreme), 3- Impact - (0= None to 6 = extreme) and 4-Importance (0= None to 6 = extreme). The numbers were summative and are input to the QOL calculation, which is a percentage of severity on a scale of 0-100. The mean value was taken across this population. The higher scores were a worse outcome.

Sex: All, ages: 6 Years to 50 Years

Inclusion Criteria:

Individuals eligible to participate in this study must meet all the following inclusion criteria:

1. Participated in the SMA-001 study
2. 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.
3. Female patients of childbearing potential must have a negative pregnancy test (urine human chorionic gonadotropin \[HCG\] at the end of SMA-001 study); and must practice an effective, reliable contraceptive regimen during the study and for up to 30 days following discontinuation of treatment.
4. 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:

Individuals who met any of the exclusion criteria in the original protocol or those listed below are not eligible to participate in the study:

1. Epilepsy and currently on medication.
2. Uncontrolled asthma.
3. Concomitant use with sultopride.
4. Concomitant use with medicinal products with a narrow therapeutic window.
5. Concomitant use with medicinal products with a known to cause QTc prolongation.
6. Clinically significant abnormalities in 12 lead ECG, in the opinion of the Investigator.
7. Subjects with congenital QT syndromes.
8. Breastfeeding or pregnant at Screening or planning to become pregnant at any time during the study.
9. Intolerable amifampridine-related side effects
10. Treatment with an investigational drug (other than amifampridine) or device while participating in this study.
11. 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.
12. History of drug allergy to any pyridine-containing substances or any amifampridine excipient(s).

Participant flow

Outcome results

• Long-term Safety and Tolerability of Amifampridine (Primary), Count of participants, Participants: Amifampridine Phosphate 5
• To Assess the Clinical Efficacy of Amifampridine Phosphate Over Time in Patients With SMA Type 3 Based on Changes in Quality of Life (QoL). (Secondary), Mean, score on a scale: Amifampridine Phosphate 33.737 +/- 17.677

Adverse events

Time frame: 27 months

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The results of efficacy are limited to the assessment of quality of life using the INQoL. The premature interruption of the study determined that few patients had available data of INQoL from Month 6 onwards.

• Study Protocol: original protocol (PDF, 2018-07-24)
• Study Protocol: Amendment 1 (PDF, 2019-04-12)
• Statistical Analysis Plan (PDF, 2020-06-29)

• Lorenzo Maggi, MD, Principal investigator, Carlo Besta Institute, Milan, Italy