Clinical Trial Results:
A randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of safinamide 100 mg once daily, as add-on therapy, in idiopathic Parkinson’s Disease (IPD) patients with motor fluctuations and PD related chronic pain
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Summary
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EudraCT number |
2017-002426-20 |
Trial protocol |
ES FR AT IT |
Global end of trial date |
03 May 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
16 Dec 2021
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First version publication date |
16 Dec 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
Z7219M01
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03841604 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Zambon SpA
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Sponsor organisation address |
Via Antonio Meucci, 3, Bresso (Milan), Italy, 20091
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Public contact |
Clinical Development Manager , Zambon SpA, clinicaltrials@zambongroup.com
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Scientific contact |
Clinical Development Manager , Zambon SpA, clinicaltrials@zambongroup.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
18 Oct 2021
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
03 May 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Primary:
• The change from baseline to Week 16 in pain severity, as assessed with an 11-point NRS.
Secondary:
• Subjects with reduction in pain severity of ≥2 points at Week 16, as assessed with an 11-point NRS, compared to baseline.
• The Clinical Global Impression of Severity (CGI-S) score for pain at Week 16.
• The change from baseline to Week 16 in the Clinical Global Impression of Change (CGI-C) score for pain.
• The change from baseline to Week 16 in the Patient Global Impression of Change (PGI-C) score for pain.
• The percentage of reduction in number of concomitant pain drugs from baseline to Week 16.
• The number of patients with at least one intake of PRN pain medication.
• Amount of PRN pain medication.
• The change from baseline to Week 16 in the Hospital Anxiety and Depression Scale (HADS) score.
• The change from baseline to Week 16 in the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale during the “ON” phase.
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Protection of trial subjects |
Written consent was obtained from the patient before he/she could participate in the study. The content and process of obtaining informed consent was in accordance with all applicable regulatory requirements.
Prior to the initiation of any procedures relating to the study, a patient’s consent was obtained using a consent form written in the patient’s native language that was approved by the institutional review boards (IRBs)/independent ethics committee (IEC) and that was signed and personally dated by the patient at the time of consent. The person who conducted the informed consent discussion signed and personally dated the consent form. A copy of the signed and dated informed consent was given to the patient. The Investigator kept each patient’s original, signed and dated consent form on file for inspection by a regulatory authority or authorized party at any time.
Depending on national regulations, an authorized person other than the Investigator could inform the patient, sign and date the consent form.
During the patient’s participation in the study, whenever important new information became available that was relevant to the patient’s consent, the consent form was updated accordingly for IRB/IEC approval. The patient was informed in a timely manner if new information became available that was relevant to the patient’s willingness to continue participation in the study. The communication of this information was documented. The approved revised consent form was signed and dated by the patient.
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Background therapy |
All patients were on a stable therapy with Levodopa (L-DOPA), alone or in combination with other anti Parkinson drugs. PRN PD pain medications were used as needed from Day 1 onwards, subjects recorded the use of as needed (PRN) medications along with indicating the worst pain they experienced on a daily basis. | ||
Evidence for comparator |
There is no comparator. It is a placebo-controlled study. | ||
Actual start date of recruitment |
15 Nov 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 21
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Country: Number of subjects enrolled |
Austria: 5
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Country: Number of subjects enrolled |
France: 5
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Country: Number of subjects enrolled |
Germany: 15
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Country: Number of subjects enrolled |
Italy: 25
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Worldwide total number of subjects |
71
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EEA total number of subjects |
71
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
30
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From 65 to 84 years |
38
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85 years and over |
3
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Recruitment
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Recruitment details |
A total of 94 subjects were enrolled in the study. 47 subjects were randomly assigned to safinamide and 25 subjects to placebo for a treatment period of 16 weeks. A screening period of up to 1 to 2 weeks was completed and reviewed to confirm each subject’s eligibility criteria. Overall, 23 subjects (24.5%) were screen failures. | |||||||||||||||||||||
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Pre-assignment
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Screening details |
About 132 participants were screened, 105 were enrolled Study participation with up to a maximum duration of 19 weeks, comprising a screening period (1 to 2 weeks) and a treatment period (16 weeks). A telephone call was performed 1 week after the end of treatment. | |||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Investigator, Monitor, Assessor, Subject | |||||||||||||||||||||
Blinding implementation details |
This was a double-blind study. The IWRS was programmed with blind-breaking instructions. In case of an emergency, the investigator had the sole responsibility for determining whether unblinding of a subject’s treatment assignment was warranted. Subject safety was always the first consideration in making such a determination.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Safinamide (50 mg and 100mg) | |||||||||||||||||||||
Arm description |
Eligible subjects were randomly assigned in a double-blind manner in a 2:1 ratio to receive treatment with safinamide at Visit 2 (Day 1), | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Safinamide methanesulfonate 50mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Safinamide methanesulfonate 50 mg tablets was administered orally, OD, with or without food, at breakfast time when the subject was taking their morning dose of L-DOPA.
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Investigational medicinal product name |
Safinamide methanesulfonate 100mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Safinamide methanesulfonate 50 mg tablets was administered orally, OD, with or without food, at breakfast time when the subject was taking their morning dose of L-DOPA.
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Arm title
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Placebo (50mg and 100 mg) | |||||||||||||||||||||
Arm description |
Eligible subjects were randomly assigned in a double-blind manner in a 2:1 ratio to receive treatment with placebo at Visit 2 (Day 1). | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo (50mg)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo (50 mg tablets) was administered orally, OD, with or without food, at breakfast time when the subject was taking their morning dose of L-DOPA.
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Investigational medicinal product name |
Placebo (100mg)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo (100 mg tablets) was administered orally, OD, with or without food, at breakfast time when the subject was taking their morning dose of L-DOPA.
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Baseline characteristics reporting groups
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Reporting group title |
Safinamide (50 mg and 100mg)
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Reporting group description |
Eligible subjects were randomly assigned in a double-blind manner in a 2:1 ratio to receive treatment with safinamide at Visit 2 (Day 1), | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo (50mg and 100 mg)
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Reporting group description |
Eligible subjects were randomly assigned in a double-blind manner in a 2:1 ratio to receive treatment with placebo at Visit 2 (Day 1). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Full analysis set (FAS)
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All randomized subjects in the study, with at least one measurement of the primary efficacy variable following at least one dose of study drug, were included in the full analysis set (FAS). Summaries on the FAS were performed for all efficacy endpoints. Subjects in this analysis set were summarized according to the treatment to which they were randomly assigned.
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Subject analysis set title |
Per-protocol Set (PPS)
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The per-protocol (PP) set was a subset of subjects in the FAS who completed the study and for whom no relevant protocol deviations were documented. Identification of relevant protocol deviations occurred during a blinded review meeting that preceded database lock. A second analysis of the primary efficacy endpoint was based on the PP set. All subjects in the PP set were summarized according to the treatment to which they were assigned.
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Subject analysis set title |
Safety Set
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The safety set included all randomized subjects assigned to study drug who took at least 1 dose of study drug. The safety set was used for the analysis of all safety endpoints.
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End points reporting groups
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Reporting group title |
Safinamide (50 mg and 100mg)
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Reporting group description |
Eligible subjects were randomly assigned in a double-blind manner in a 2:1 ratio to receive treatment with safinamide at Visit 2 (Day 1), | ||
Reporting group title |
Placebo (50mg and 100 mg)
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Reporting group description |
Eligible subjects were randomly assigned in a double-blind manner in a 2:1 ratio to receive treatment with placebo at Visit 2 (Day 1). | ||
Subject analysis set title |
Full analysis set (FAS)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All randomized subjects in the study, with at least one measurement of the primary efficacy variable following at least one dose of study drug, were included in the full analysis set (FAS). Summaries on the FAS were performed for all efficacy endpoints. Subjects in this analysis set were summarized according to the treatment to which they were randomly assigned.
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Subject analysis set title |
Per-protocol Set (PPS)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The per-protocol (PP) set was a subset of subjects in the FAS who completed the study and for whom no relevant protocol deviations were documented. Identification of relevant protocol deviations occurred during a blinded review meeting that preceded database lock. A second analysis of the primary efficacy endpoint was based on the PP set. All subjects in the PP set were summarized according to the treatment to which they were assigned.
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Subject analysis set title |
Safety Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The safety set included all randomized subjects assigned to study drug who took at least 1 dose of study drug. The safety set was used for the analysis of all safety endpoints.
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End point title |
Change from baseline to week 16 in pain severity (FAS) | |||||||||||||||
End point description |
The primary endpoint evaluated in this study was the mean change in pain severity (“average worst pain experienced in the last 7 days”, ie, average of the worst pain score on each of the 7 days preceding the site visit), as assessed by an 11-point NRS, from baseline to Week 16
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End point type |
Primary
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End point timeframe |
From baseline to Week 16
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Statistical analysis title |
Difference in Change from Baseline at week 16 | |||||||||||||||
Statistical analysis description |
The primary efficacy endpoint was analyzed with a mixed model for repeated measures (MMRM), using visit on subject ID as the repeated factor with an unstructured covariance term. The model included fixed effects terms for treatment, country, visit, and regular pain medication use at baseline (yes or no) and a covariate term for pain severity score at baseline.
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Comparison groups |
Safinamide (50 mg and 100mg) v Placebo (50mg and 100 mg)
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Number of subjects included in analysis |
68
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.1695 [1] | |||||||||||||||
Method |
Mixed Model Repeated Measures | |||||||||||||||
Parameter type |
Least Squares (LS) Means | |||||||||||||||
Point estimate |
-0.7
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-1.75 | |||||||||||||||
upper limit |
0.32 | |||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.52
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| Notes [1] - p-value at Week 16 is used for testing the null hypothesis for the primary endpoint that safinamide is no better than placebo in managing pain. p-value derived for the difference between treatment groups at each visit. |
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End point title |
Change from baseline to week 16 in pain severity (PP set) | |||||||||||||||
End point description |
The Per Protocol (PP) Set is a subset of subjects in the FAS who signed the ICF, completed the study i.e. follow-up visit after Week 16, received the treatment as per IVRS, had more than 80% study medication compliance at all visit-to-visit interval, had at least 4 out of 7 pain score available at baseline and Week 16 and for whom no major protocol deviations were documented.
Average worst Pain Score is calculated using 11-point NRS Scale by taking average of scores obtained in last 7 days before each visit.
At least 4 out of 7 daily pain scores are needed to calculate a valid average over 7 days.
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End point type |
Primary
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End point timeframe |
From baseline until Week 16
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Statistical analysis title |
Difference in Change from Baseline at week 16 | |||||||||||||||
Statistical analysis description |
The primary efficacy endpoint was analyzed with a mixed model for repeated measures (MMRM), using visit on subject ID as the repeated factor with an unstructured covariance term. The model included fixed effects terms for treatment, country, visit, and regular pain medication use at baseline (yes or no) and a covariate term for pain severity score at baseline.
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Comparison groups |
Safinamide (50 mg and 100mg) v Placebo (50mg and 100 mg)
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Number of subjects included in analysis |
54
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.0784 [2] | |||||||||||||||
Method |
Mixed Model Repeated Measures | |||||||||||||||
Parameter type |
Least Squares (LS) Mean | |||||||||||||||
Point estimate |
-1
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-2.1 | |||||||||||||||
upper limit |
0.12 | |||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.55
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| Notes [2] - p-value derived for the difference between treatment groups at each visit. |
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End point title |
Subjects with reduction in pain severity of ≥2 points at Week 16 | |||||||||||||||
End point description |
Subjects with reduction in pain severity of ≥2 points (“average worst pain experienced in the last 7 days”) at Week 16, as assessed with an 11-point NRS, compared to baseline.
Missing values at each visit for Observed Responder are not used in CMH calculation.
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End point type |
Secondary
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End point timeframe |
At week 16
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Statistical analysis title |
Percentages of Pain Responders | |||||||||||||||
Statistical analysis description |
Percentage of pain responders, defined as subjects with reduction in pain severity of ≥2 points from baseline (“average worst pain experienced in the last 7 days”), as assessed with an 11-point NRS, was analyzed at Week 16 using a Cochran-Mantel-Haenszel (CMH) adjusted test of the difference in proportions between the 2 treatment groups. Country was used as the stratification factor.
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Comparison groups |
Placebo (50mg and 100 mg) v Safinamide (50 mg and 100mg)
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Number of subjects included in analysis |
68
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.0744 [3] | |||||||||||||||
Method |
Cochran-Mantel-Haenszel | |||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||
Point estimate |
-0.23
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-0.45 | |||||||||||||||
upper limit |
-0.01 | |||||||||||||||
| Notes [3] - p-value derived from the 2-sided Cochran-Mantel-Haenszel (CMH) test to test the null hypothesis of no difference between treatment groups in percentage of pain responder rates adjusted for country as stratification factor |
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End point title |
The Clinical Global Impression of Severity (CGI-S) score for pain at Week 16 | ||||||||||||||||||
End point description |
The CGI-S was analyzed using the same statistical methods, ie, MMRM as for the primary efficacy parameter by replacing the covariate of pain severity at baseline with the respective efficacy parameter.
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End point type |
Secondary
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End point timeframe |
From baseline to week 16
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Statistical analysis title |
Analysis of Clinical Global Impression of Severity | ||||||||||||||||||
Statistical analysis description |
The Clinical Global Impression of Severity (CGI-S) score for pain was analyzed with a mixed model for repeated measures (MMRM). The model included fixed effects terms for treatment, country, visit, and regular pain medication use at baseline (yes or no) and a covariate term for pain severity score at baseline.
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Comparison groups |
Safinamide (50 mg and 100mg) v Placebo (50mg and 100 mg)
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Number of subjects included in analysis |
59
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.9052 [4] | ||||||||||||||||||
Method |
Mixed Model Repeated Measures | ||||||||||||||||||
Parameter type |
Least Squares (LS) Mean | ||||||||||||||||||
Point estimate |
0
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
-0.43 | ||||||||||||||||||
upper limit |
0.38 | ||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.2
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| Notes [4] - p-value derived for the difference between treatment groups at each visit. |
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End point title |
The change from baseline to Week 16 in the Clinical Global Impression of Change (CGI-C) score for pain. | |||||||||||||||
End point description |
The CGI-C was analyzed using the same statistical methods, ie, MMRM as for the primary efficacy parameter by replacing the covariate of pain severity at baseline with the respective efficacy parameter.
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End point type |
Secondary
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End point timeframe |
From baseline to Week 16
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Statistical analysis title |
Analysis of Clinical Global Impression of Change | |||||||||||||||
Statistical analysis description |
The change from baseline to Week 16 in the Clinical Global Impression of Change (CGI-C) score for pain was analyzed with a mixed model for repeated measures (MMRM). The model included fixed effects terms for treatment, country, visit, and regular pain medication use at baseline (yes or no) and a covariate term for pain severity score at baseline.
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Comparison groups |
Placebo (50mg and 100 mg) v Safinamide (50 mg and 100mg)
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Number of subjects included in analysis |
57
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.7247 [5] | |||||||||||||||
Method |
Mixed model for repeated measures | |||||||||||||||
Parameter type |
Least Squares (LS) Mean | |||||||||||||||
Point estimate |
-0.1
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
-0.7 | |||||||||||||||
upper limit |
0.49 | |||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||
Dispersion value |
0.3
|
|||||||||||||||
| Notes [5] - p-value derived for the difference between treatment groups at each visit. |
||||||||||||||||
|
||||||||||||||||
End point title |
The change from baseline to Week 16 in the Patient Global Impression of Change (PGI-C) score for pain. | |||||||||||||||
End point description |
The PGI-C was analyzed using the same statistical methods, ie, MMRM as for the primary efficacy parameter by replacing the covariate of pain severity at baseline with the respective efficacy parameter.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From baseline to week 16
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
Analysis of Patient Global Impression of Change | |||||||||||||||
Statistical analysis description |
The change from baseline to Week 16 in the Patient Global Impression of Change (PGI-C) score for pain was analyzed with a mixed model for repeated measures (MMRM). The model included fixed effects terms for treatment, country, visit, and regular pain medication use at baseline (yes or no) and a covariate term for pain severity score at baseline.
|
|||||||||||||||
Comparison groups |
Placebo (50mg and 100 mg) v Safinamide (50 mg and 100mg)
|
|||||||||||||||
Number of subjects included in analysis |
53
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
superiority | |||||||||||||||
P-value |
= 0.7115 [6] | |||||||||||||||
Method |
Mixed model for repeated measures | |||||||||||||||
Parameter type |
Least Squares (LS) Mean | |||||||||||||||
Point estimate |
0.1
|
|||||||||||||||
Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
-0.61 | |||||||||||||||
upper limit |
0.88 | |||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||
Dispersion value |
0.37
|
|||||||||||||||
| Notes [6] - p-value derived for the difference between treatment groups at each visit. |
||||||||||||||||
|
||||||||||||||||
End point title |
The percentage of reduction in number of concomitant pain drugs from baseline to Week 16. | |||||||||||||||
End point description |
The analysis of concomitant pain drugs (as reported on the concomitant medications page in the eCRF) were summarized in the number of subjects who were taking pain medication in the 7 days preceding visits.
The statistical analysis is not estimable.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From baseline to week 16
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
||||||||||||||||
End point title |
The number of patients with at least one intake of PRN pain medication. | |||||||||||||||
End point description |
The analysis of amount of concomitant PRN PD pain medications (as reported in the subject diary) was summarized in the number of days on which pain medication was taken in the number of subjects who were taking pain medication in the 7 days preceding visits.
Missing values at each visit for subjects with no data are not used in CMH calculation.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From baseline to week 16
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
Analysis of the Amount of PRN PD Pain Medication | |||||||||||||||
Statistical analysis description |
95% CI and p-value for number of subjects with PRN PD Pain medication derived from the 2-sided Cohran-Mantel-Haenszel (CMH) test to test the null hypothesis of no difference between treatment groups in percentage of subjects who has taken and not taken PRN PD pain medication adjusted for country as stratification factor.
|
|||||||||||||||
Comparison groups |
Placebo (50mg and 100 mg) v Safinamide (50 mg and 100mg)
|
|||||||||||||||
Number of subjects included in analysis |
68
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
superiority | |||||||||||||||
P-value |
= 0.5215 [7] | |||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | |||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||
Point estimate |
0.08
|
|||||||||||||||
Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
-0.18 | |||||||||||||||
upper limit |
0.34 | |||||||||||||||
| Notes [7] - p-value for number of days on which PRN PD pain medication was taken, are calculated using a two-sided Mann Whitney test to test the null hypothesis of no difference between the two treatments. |
||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Number of subjects using PRN | ||||||||||||||||||||||||||||||
End point description |
The analysis of amount of concomitant PRN PD pain medications (as reported in the subject diary) was summarized in the number of days on which pain medication was taken in the number of subjects who were taking pain medication in the 7 days preceding visits.
Missing values at each visit for subjects with no data are not used in CMH calculation.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
From baseline to week 16
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Statistical analysis title |
Analysis of the Amount of PRN PD Pain Medication | ||||||||||||||||||||||||||||||
Statistical analysis description |
95% CI and p-value for number of subjects with PRN PD Pain medication derived from the 2-sided Cohran-Mantel-Haenszel (CMH) test to test the null hypothesis of no difference between treatment groups in percentage of subjects who has taken and not taken PRN PD pain medication adjusted for country as stratification factor.
|
||||||||||||||||||||||||||||||
Comparison groups |
Safinamide (50 mg and 100mg) v Placebo (50mg and 100 mg)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
68
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||
P-value |
= 0.5122 [8] | ||||||||||||||||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||
Point estimate |
0.06
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.13 | ||||||||||||||||||||||||||||||
upper limit |
0.26 | ||||||||||||||||||||||||||||||
| Notes [8] - p-value for number of days on which PRN PD pain medication was taken, are calculated using a two-sided Mann Whitney test to test the null hypothesis of no difference between the two treatments |
|||||||||||||||||||||||||||||||
|
||||||||||||||||
End point title |
The change from baseline to Week 16 in the Hospital Anxiety and Depression Scale (HADS) score. | |||||||||||||||
End point description |
Change from baseline in HADS score at Week 16 was analyzed using an ANCOVA model. The model included treatment, baseline HADS, and country as fixed effects.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From baseline to week 16
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
ANCOVA Analysis of HADS Score | |||||||||||||||
Statistical analysis description |
The analysis of covariance (ANCOVA) model for sensitivity analysis of the primary efficacy endpoint included fixed effects terms for treatment, country, and visit and a covariate term for pain severity score at baseline. The ANCOVA model for the secondary efficacy endpoint (change from baseline in HADS at Week 16) included treatment, baseline HADS, and country as fixed effects.
|
|||||||||||||||
Comparison groups |
Safinamide (50 mg and 100mg) v Placebo (50mg and 100 mg)
|
|||||||||||||||
Number of subjects included in analysis |
53
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
superiority | |||||||||||||||
P-value |
= 0.7376 [9] | |||||||||||||||
Method |
ANCOVA | |||||||||||||||
Parameter type |
Least Squares (LS) Mean | |||||||||||||||
Point estimate |
-0.4
|
|||||||||||||||
Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
-3.03 | |||||||||||||||
upper limit |
2.16 | |||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||
Dispersion value |
1.29
|
|||||||||||||||
| Notes [9] - p-value derived for the difference between treatment groups at Week 16. |
||||||||||||||||
|
||||||||||||||||
End point title |
The change from baseline to Week 16 in the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale during the “ON” phase. | |||||||||||||||
End point description |
The change from baseline to Week 16 in the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS; total score and subscores) during the “ON” phase.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
From Baseline to week 16
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
MMRM Analysis of MDS-UPDRS | |||||||||||||||
Statistical analysis description |
The MDS-UPDRS was analyzed with a mixed model for repeated measures (MMRM). The model included fixed effects terms for treatment, country, visit, and regular pain medication use at baseline (yes or no) and a covariate term for pain severity score at baseline.
|
|||||||||||||||
Comparison groups |
Safinamide (50 mg and 100mg) v Placebo (50mg and 100 mg)
|
|||||||||||||||
Number of subjects included in analysis |
50
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
superiority | |||||||||||||||
P-value |
= 0.5349 [10] | |||||||||||||||
Method |
Mixed Model Repeated Measures | |||||||||||||||
Parameter type |
Least Squares (LS) Mean | |||||||||||||||
Point estimate |
-2.5
|
|||||||||||||||
Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
-10.33 | |||||||||||||||
upper limit |
5.43 | |||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||
Dispersion value |
3.92
|
|||||||||||||||
| Notes [10] - p-value derived for the difference between treatment groups at each visit. |
||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Treatment-Emergent Adverse Events (TEAEs) were summarized for the on-treatment period (Day 1 to Week 16)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Overall, 43.7% of subjects had TEAEs, and the incidence was higher in the placebo group than in the safinamide group (48.0% versus 41.3%). Overall, 11.3% of subjects had TEAEs that led to treatment discontinuation and 7.0% to study discontinuation/early withdrawal, and no subjects died during the study. Overall, safinamide was found well tolerated.
|
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
|
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Reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Safinamide
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
The study drugs administered to subjects in this study were safinamide 50 mg or 100 mg tablets. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
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Reporting group description |
The study drugs administered to subjects in this study were placebo 50 mg or 100 mg tablets. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 1% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
10 Oct 2019 |
The first protocol amendment (dated 10 Oct 2019) was applicable to all countries where the study was conducted, except France. Amendment 1 was effective before the first subject was screened for the study.
The major changes to the protocol amendment 1 are the following:
- Rewording - to better reflect the endpoint data collected.
- Inclusion Criteria - updated to reflect the SmPC and to better clarify the criteria
- Exclusion Criteria - updated to grater clarity and to expand eligibility of patients without compromising the quality of the trial.
- Screen Failure - Sentence rephrased to allow rescreening, defining times and time frame.
- Study Intervention(s) Administered - updated to match with the update of IMPD
- Concomitant Therapy and Excluded Medicine - Wording was added to better clarify the use of combination analgesic therapy.
- Time Period and Frequency for Collecting AE and SAE Information - Paragraph 2 was deleted to conform with standard reporting AEs.
- Regulatory Reporting Requirements for SAEs - Reference Safety Information added to specify the reference safety information for this study.
- Appendix 3 Subsection “Assessment of Causality” and References - modified to delete Investigator’s Brochure and left only SmPC, since SmPC was the reference safety information for this study. |
||
27 Oct 2020 |
A France-specific Protocol Amendment 1 and Protocol Amendment 2 for other countries were made on 27 Oct 2020.
The major Changes in France-specific Protocol Amendment 1 and Protocol Amendment 2 for Other Countries are the following:
- Study Synopsis - Paragraph “number of participant” and Overall Design - Sample size was recalculated based on blind data review performed as recommended by FDA guidelines for studies conducted during COVID-19 emergency.
- Schedules of Activities - Cross-reference to contingency plan (Appendix 10) was added. A contingency plan was developed to mitigate impact of COVID-19 emergency on the study visits; it described the measures to be adopted to keep patients in the study and mitigate countries’ restrictions. Contingency plan was notified to sites when needed, but now it was attached to protocol for a quicker access and consultation.
- Preparation / handling / storage / accountability ; Study Assessments and Procedures and Appendix 10, Contingency Plan - updated based on the above defined for contingency plan.
- Sample Size Determination - Since Mar 2020, COVID-19 emergency impacted the feasibility of trial that were conducted in a vulnerable group of patients. FDA released guidelines with the aim of helping sponsors ensure that trials conducted during the COVID-19 emergency continue, where appropriate, to provide interpretable findings with correct statistical quantification of uncertainty.
- Population of Analyses and Statistical Analyses - Wording was aligned with SAP to achieve consistency across the study documents.
- References - FDA guideline was listed among the references as it was adopted for the sample size re-calculation
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
