Safinamide for Multiple System Atrophy (MSA)

The overall design is a parallel group, placebo controlled, double blind study. The target population are participants diagnosed with possible or probable parkinsonian variant of Multiple System Atrophy who are on stable doses of levodopa.

Trial participation will be up to a maximum duration of 14 weeks and will comprise a screening period (up to 2 weeks), a 2-week run in period during which subjects will receive 1 tablet (either 100 mg safinamide or matching placebo), followed by a 10-week period, during which study participants will take 2 tablets of study medication (200 mg safinamide or placebo) once daily, taken in the morning in addition to their morning levodopa dose. A telephone follow-up call will be performed 2 weeks after the end of treatment.

• Safinamide Methanesulfonate (Drug), also known as Xadago: 100 mg (free base)
• Safinamide Methanesulfonate matching placebo (Drug), also known as placebo: 100 mg placebo

Primary outcomes

• TEAEs (Treatment Emergent Adverse Events) and SAEs (Serious Adverse Events) [Throughout the study, from baseline (and at each interim visit) to telephone follow-up visit at 14 week.]: While evaluating safety and tolerability of safinamide, 200 mg od, compared with placebo, severity of TEAEs, their relationship to study drug, their seriousness and their consequences were assessed. TEAEs were defined as adverse events (AEs) that started after the first dose of study drug.

Secondary outcomes

• Change From Baseline to Week 12 in the Goniometric Measurement for Anterior Displacement [From baseline to week 12]: To evaluate the potential efficacy of safinamide 200 mg od, as add-on therapy, on quality of life (change in anterior displacement). The goniometric measurement consists in the posture evaluation of the patient, measuring through a goniometer the angle of the flexion of the trunk. Goniometric measurement of "anterior" displacement was determined using a wall goniometer and expressing the value in degrees in the range of 0 to 90.
• Change From Baseline to Week 12 in the Goniometric Measurement for Lateral Displacement [From baseline to week 12]: To evaluate the potential efficacy of safinamide 200 mg od, as add-on therapy, on quality of life (change in anterior displacement). The goniometric measurement consists in the posture evaluation of the patient, measuring through a goniometer the angle of the flexion of the trunk. Goniometric measurement of "lateral" displacement was determined using a wall goniometer and expressing the value in degrees in the range of 0 to 90.
• Change From Baseline to Week 12 in Unified Multiple System Atrophy Rating Scale (UMSARS), Part II (ITT Population) [From baseline to week 12]: UMSARS is a validated, disease-specific scale representing the diverse signs and symptoms in MSA. Higher scores on the UMSARS scales mean poorer health. UMSARS has the following domains: Part I - Activities of Daily Living score (12 questions ranged in 0-4 \[total score 0-48\]) that evaluates motor including autonomic activities Part II - Motor Examination score (14 questions, \[total score 0-56\]) Part III - Autonomic Examination Part IV - Global disability scale ((1=completely independent; 2=not completely independent; 3=more dependent; 4=very dependent; 5=total dependent and helpless). Only UMSARS Part II total score is reported, which was obtained as the sum of the 14 items in the scale. If any of the items were missing, then the total score was considered missing. Higher scores indicate worse functional situation.
• Change From Baseline to Week 12 in Unified Multiple System Atrophy Rating Scale (UMSARS), Part II (PP Population) [From baseline to week 12]: UMSARS is a validated, disease-specific scale representing the diverse signs and symptoms in MSA. Higher scores on the UMSARS scales mean poorer health. UMSARS has the following domains: Part I - Activities of Daily Living score (12 questions ranged in 0-4 \[total score 0-48\]) that evaluates motor including autonomic activities Part II - Motor Examination score (14 questions, \[total score 0-56\]) Part III - Autonomic Examination Part IV - Global disability scale ((1=completely independent; 2=not completely independent; 3=more dependent; 4=very dependent; 5=total dependent and helpless). Only UMSARS Part II total score is reported, which was obtained as the sum of the 14 items in the scale. If any of the items were missing, then the total score was considered missing. Higher scores indicate worse functional situation.
• Change From Baseline to Week 12 in Multiple System Atrophy Health-Related Quality of Life (MSA-QoL) Scale [From baseline to week 12]: The MSA-QoL is a self-reported questionnaire focusing on MSA-specific symptoms and has a scale ranging from 0 to 160, with 0= 'no problem' and 160= "extreme problem".
• Change From Baseline to Week 12 in Montreal Cognitive Assessment (MoCA) Scale [From baseline to week 12]: The Montreal Cognitive Assessment (MoCA) was designed as a tool for rapid screening for mild cognitive impairment. It evaluates different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructive skills, abstraction, calculation and orientation. The administration time of the MoCa is 10 minutes. The MoCA scale ranges from 0 to 30, with higher scores indicating better cognitive functioning.
• Change From Baseline to Week 12 in Unified Dystonia Rating Scale (UDRS) [From baseline to week 12]: UDRS consists of a Historical Section, divided into questionnaires about 1) on-dyskinesia and 2) off -dystonia, and an Objective Section, divided into 3) impairment and 4) disability scales. The Historical Section is scored from 0-60, and the Objective section is scored 0-44, where higher scores reflect greater difficulty or impairment. The Unified Dystonia Rating Scale (UDRS) assesses the motor severity and duration of dystonia in 14 body areas. The total score, obtained as the sum of the severity and duration factors, ranges from 0 to 112. Higher scores indicate worse dystonia.

Sex: All, ages: 30 Years to 80 Years

Inclusion Criteria:

1. Participant must be 30 to 80 years of age inclusive, at the time of signing the informed consent;
2. Participants who are diagnosed (with MRI confirmation) with possible or probable parkinsonian variant of Multiple System Atrophy less than 2 years ago;
3. Participants with an anticipated survival of at least 3 years in the opinion of the investigator;
4. Female not pregnant, not breastfeeding, and at least one of the following conditions applies:

   * Not a woman of childbearing potential OR
   * A woman of childbearing potential who agrees to follow the contraceptive guidance during the treatment period and for at least 30 days after the last dose of study intervention;
5. Capable of giving signed informed consent

Exclusion Criteria:

1. History of neurosurgical procedure, including stereotactic surgery;
2. History of Deep Brain Stimulation (DBS);
3. History of bipolar disorder, severe depression, schizophrenia or other psychotic disorder;
4. History of drug and/or alcohol abuse within 12 months prior to screening as defined by the current edition of the Diagnostic and Statistical Manual of Mental Disorders;
5. History of dementia (DSM-V criteria);
6. Ophthalmologic history including any of the following conditions: albinism, uveitis, retinitis pigmentosa, retinal degeneration, active retinopathy, severe progressive diabetic retinopathy, inherited retinopathy or family history of hereditary retinal disease;
7. Active hepatitis B or C;
8. History of human immunodeficiency virus (HIV) infection;
9. Subjects not able to swallow oral medications;
10. Subjects with severe orthostatic symptoms;
11. Impaired ambulation, i.e. falling more than once per week, bedridden patients or confined to a wheelchair during the whole day;
12. Subjects with active malignant neoplasms;
13. Movement disorders other than MSA (e.g. Parkinson Disease, dementia with Lewy bodies, essential tremor, progressive supranuclear palsy, pharmacological or post-encephalic parkinsonism);
14. Any clinically significant or unstable medical or surgical condition that, in the opinion of the investigator, might preclude safe completion of the study or might affect the results of the study;
15. Not on a stable regime, for at least 4 weeks prior to the randomization (baseline visit), of

    1. oral levodopa (including controlled release, immediate release or a combination of controlled release/immediate release), with or without benserazide/carbidopa, with or without addition of a catechol O-methyltransferase (COMT) inhibitor or
    2. dopamine agonist, anticholinergic and/or amantadine.
16. Patients should not have received treatment with monoamine oxidase inhibitors in the 2 weeks prior to the randomization visit, nor treatment with levodopa infusion, pethidine, opiates, opioids, fluoxetine, fluvoxamine in the 4 weeks prior to the randomization visit;
17. Patients should not have received treatment with an oral or depot neuroleptic within 12 weeks prior to the randomization visit;
18. Use of any investigational drug within 30 days prior to screening or 5 half-lives, whichever is the longest;
19. Montreal Cognitive Assessment (MoCA) ≤ 20;
20. Laboratory assessments showing moderate or severe hepatic impairment (2x ULN);
21. Allergy/sensitivity or contraindications to the investigational medicinal products (IMPs) or their excipients, anticonvulsants, levodopa or other anti-parkinsonian drugs;
22. Any clinically significant condition which, in the opinion of the Investigator, would not be compatible with study participation or represent a risk for patients while in the study.

Participant flow

Outcome results

• TEAEs (Treatment Emergent Adverse Events) and SAEs (Serious Adverse Events) (Primary), Number, events: Safinamide 52; Placebo 28
• Change From Baseline to Week 12 in the Goniometric Measurement for Anterior Displacement (Secondary), Mean, degrees: Safinamide 1.3 +/- 9.46; Placebo 0.9 +/- 8.01 (p 0.9697)
• Change From Baseline to Week 12 in the Goniometric Measurement for Lateral Displacement (Secondary), Mean, degrees: Safinamide 1.3 +/- 5.08; Placebo -0.2 +/- 4.47 (p 0.7751)
• Change From Baseline to Week 12 in Unified Multiple System Atrophy Rating Scale (UMSARS), Part II (ITT Population) (Secondary), Mean, score on a scale: Safinamide -0.1 +/- 5.40; Placebo -0.4 +/- 5.85 (p 0.9076)
• Change From Baseline to Week 12 in Unified Multiple System Atrophy Rating Scale (UMSARS), Part II (PP Population) (Secondary), Mean, score on a scale: Safinamide -1.1 +/- 4.66; Placebo -0.6 +/- 6.17 (p 0.5386)
• Change From Baseline to Week 12 in Multiple System Atrophy Health-Related Quality of Life (MSA-QoL) Scale (Secondary), Mean, units on a scale: Safinamide 5.6 +/- 25.57; Placebo -2.9 +/- 14.37 (p 0.3364)
• Change From Baseline to Week 12 in Montreal Cognitive Assessment (MoCA) Scale (Secondary), Mean, score on a scale: Safinamide 0.0 +/- 2.01; Placebo -0.3 +/- 2.09 (p 0.7574)
• Change From Baseline to Week 12 in Unified Dystonia Rating Scale (UDRS) (Secondary), Mean, units on a scale: Safinamide 1.0 +/- 4.82; Placebo 0.3 +/- 5.60 (p 0.6393)

Adverse events

Time frame: At baseline, at interim visits (Weeks 2 - 8, and more precisely at days 14 ± 3, 28 ± 3, 56 ± 3), at End of Treatment visit (EOT) at Week 12 (84 ± 3 days), and at follow-up call at week 14 ( 98 ± 3).

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2020-07-13)
• Statistical Analysis Plan (PDF, 2021-01-20)

• Charlotte Keywood, MD, Study director, Zambon SpA

NIH grants: 2018