Clinical Trial Results:
A Dose Escalation, Proof of Concept, Phase IIA Study to Investigate the Safety and Tolerability, the Pharmacokinetic and the Pharmacodynamic of BN82451B, Administered Twice Daily Over 4 Weeks, in Male Patients with Huntington's Disease
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Summary
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EudraCT number |
2013-002899-41 |
Trial protocol |
DE |
Global end of trial date |
31 Mar 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
26 Apr 2017
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First version publication date |
26 Apr 2017
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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 |
8-55-52966-005
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02231580 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Ipsen Pharma
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Sponsor organisation address |
65 Quai Georges Gorse, Boulogne-Billancourt, France, 92100
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Public contact |
Vice President Early Development & Clinical Pharmacology, Ipsen Pharma, clinical.trials@ipsen.com
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Scientific contact |
Vice President Early Development & Clinical Pharmacology, Ipsen Pharma, clinical.trials@ipsen.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 |
31 Mar 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Mar 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Mar 2016
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To evaluate the safety and tolerability of BN82451B versus placebo after oral administration twice daily (b.i.d) for 28 days in subjects with Huntington's Disease (HD).
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Protection of trial subjects |
The clinical study was conducted in accordance with the International Conference on Harmonisation Consolidated Guideline on Good Clinical Practice, under the ethical principles laid down in the Declaration of Helsinki. In addition, this clinical study adhered to all local regulatory requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Sep 2014
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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 |
Germany: 17
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Worldwide total number of subjects |
17
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EEA total number of subjects |
17
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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) |
17
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was a double blind, placebo controlled, randomised, sequential dose ranging repeated dose trial where patients were recruited to a single study centre in Germany. It was planned to enrol 30 patients (10 in each of 3 cohorts). Patients were enrolled to the study from 1 September 2014 until early termination of the study on 31 March 2016. | |||||||||||||||||||||
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Pre-assignment
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Screening details |
Male patients 20-70 years with a documented diagnosis of HD with at least 36 cytosine adenine guanine repeats in the Huntington gene were screened. Eligibile patients needed to meet defined criteria during quantitative motor function assessments. 25 patients were screened, 17 were enrolled and randomised to treatment. | |||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (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 |
Subject, Investigator | |||||||||||||||||||||
Blinding implementation details |
The study medications were supplied in a common high density polyethylene bottle, and the placebo capsules matched the BN52451B capsules with respect to size, colour, smell, taste and appearance.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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BN82451B | |||||||||||||||||||||
Arm description |
Patients were randomised to receive oral study medication, BN82451B, b.i.d. from Day 1 to Day 27, under double-blinded conditions. On Day 28 only one morning dose of BN82451B was administered. It was planned for patients to be assigned to 3 cohorts to receive 3 dose levels ranging between 40 and 80 milligrams (mg) b.i.d. For cohort 1, 40 mg BN82451B b.i.d. was administered during the first 14 days. If this dose was well tolerated then it was increased to 60 mg b.i.d. for 13 days and one morning dose of 60 mg on Day 28. For cohort 2, 60 mg BN82451B b.i.d. was administered during the first 14 days. If 60 mg b.i.d was well tolerated then it was increased to 80 mg b.i.d. for 13 days and one morning dose of 80 mg on Day 28. For cohort 3 it was planned to administer 80 mg BN82451B b.i.d for 27 days with one morning dose of 80 mg on Day 28. The study was terminated early before completion of cohort 2. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
BN82451B
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Investigational medicinal product code |
BN82451B
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
20 mg BN82451B capsules were administered orally in planned doses of 40, 60 or 80 mg b.i.d. with a maximum of 2 glasses of water in fed conditions except on days of PK evaluations (Days 1, 7, 14, 21 and 28) where the study medication was administered with a maximum of 2 glasses of water 1 hour before breakfast or the evening meal and no additional liquid intake was allowed within 1 hour before and after study medication administration.
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Arm title
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Placebo | |||||||||||||||||||||
Arm description |
Patients were randomised to receive oral placebo b.i.d. from Day 1 to Day 27, under double-blinded conditions. On Day 28 only one morning dose of placebo was administered. It was planned for patients to be assigned to 3 cohorts to receive 3 dose levels ranging between 40 and 80 mg b.i.d. For cohort 1, 40 mg placebo b.i.d. was administered during the first 14 days. If this dose was well tolerated then it was increased to 60 mg b.i.d. for 13 days and one morning dose of 60 mg on Day 28. For cohort 2, 60 mg placebo b.i.d. was administered during the first 14 days. If 60 mg b.i.d was well tolerated then it was increased to 80 mg b.i.d. for 13 days and one morning dose of 80 mg on Day 28. For cohort 3 it was planned to administer 80 mg placebo b.i.d for 27 days with one morning dose of 80 mg on Day 28. The study was terminated early before completion of cohort 2. | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
Placebo
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Matching placebo capsules were administered orally b.i.d. with a maximum of 2 glasses of water in fed conditions except on days of PK evaluations (Days 1, 7, 14, 21 and 28) where the study medication was administered with a maximum of 2 glasses of water 1 hour before breakfast or the evening meal and no additional liquid intake was allowed within 1 hour before and after study medication administration.
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| Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: The first milestone represents the number of patients who were randomised to receive BN82451B in the first cohort. The numbers of patients in the overall period includes the number of patients in milestone 1 and 2. [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: The second milestone represents the number of patients who were randomised to receive placebo in the second cohort. The numbers of patients in the overall period includes the number of patients in milestone 1 and 2. [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: The second milestone represents the number of patients who were randomised to receive BN82451B in the second cohort. The numbers of patients in the overall period includes the number of patients in milestone 1 and 2. [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: The first milestone represents the number of patients who were randomised to receive placebo in the first cohort. The numbers of patients in the overall period includes the number of patients in milestone 1 and 2. |
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Baseline characteristics reporting groups
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Reporting group title |
BN82451B
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Reporting group description |
Patients were randomised to receive oral study medication, BN82451B, b.i.d. from Day 1 to Day 27, under double-blinded conditions. On Day 28 only one morning dose of BN82451B was administered. It was planned for patients to be assigned to 3 cohorts to receive 3 dose levels ranging between 40 and 80 milligrams (mg) b.i.d. For cohort 1, 40 mg BN82451B b.i.d. was administered during the first 14 days. If this dose was well tolerated then it was increased to 60 mg b.i.d. for 13 days and one morning dose of 60 mg on Day 28. For cohort 2, 60 mg BN82451B b.i.d. was administered during the first 14 days. If 60 mg b.i.d was well tolerated then it was increased to 80 mg b.i.d. for 13 days and one morning dose of 80 mg on Day 28. For cohort 3 it was planned to administer 80 mg BN82451B b.i.d for 27 days with one morning dose of 80 mg on Day 28. The study was terminated early before completion of cohort 2. | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Patients were randomised to receive oral placebo b.i.d. from Day 1 to Day 27, under double-blinded conditions. On Day 28 only one morning dose of placebo was administered. It was planned for patients to be assigned to 3 cohorts to receive 3 dose levels ranging between 40 and 80 mg b.i.d. For cohort 1, 40 mg placebo b.i.d. was administered during the first 14 days. If this dose was well tolerated then it was increased to 60 mg b.i.d. for 13 days and one morning dose of 60 mg on Day 28. For cohort 2, 60 mg placebo b.i.d. was administered during the first 14 days. If 60 mg b.i.d was well tolerated then it was increased to 80 mg b.i.d. for 13 days and one morning dose of 80 mg on Day 28. For cohort 3 it was planned to administer 80 mg placebo b.i.d for 27 days with one morning dose of 80 mg on Day 28. The study was terminated early before completion of cohort 2. | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
BN82451B
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Reporting group description |
Patients were randomised to receive oral study medication, BN82451B, b.i.d. from Day 1 to Day 27, under double-blinded conditions. On Day 28 only one morning dose of BN82451B was administered. It was planned for patients to be assigned to 3 cohorts to receive 3 dose levels ranging between 40 and 80 milligrams (mg) b.i.d. For cohort 1, 40 mg BN82451B b.i.d. was administered during the first 14 days. If this dose was well tolerated then it was increased to 60 mg b.i.d. for 13 days and one morning dose of 60 mg on Day 28. For cohort 2, 60 mg BN82451B b.i.d. was administered during the first 14 days. If 60 mg b.i.d was well tolerated then it was increased to 80 mg b.i.d. for 13 days and one morning dose of 80 mg on Day 28. For cohort 3 it was planned to administer 80 mg BN82451B b.i.d for 27 days with one morning dose of 80 mg on Day 28. The study was terminated early before completion of cohort 2. | ||
Reporting group title |
Placebo
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Reporting group description |
Patients were randomised to receive oral placebo b.i.d. from Day 1 to Day 27, under double-blinded conditions. On Day 28 only one morning dose of placebo was administered. It was planned for patients to be assigned to 3 cohorts to receive 3 dose levels ranging between 40 and 80 mg b.i.d. For cohort 1, 40 mg placebo b.i.d. was administered during the first 14 days. If this dose was well tolerated then it was increased to 60 mg b.i.d. for 13 days and one morning dose of 60 mg on Day 28. For cohort 2, 60 mg placebo b.i.d. was administered during the first 14 days. If 60 mg b.i.d was well tolerated then it was increased to 80 mg b.i.d. for 13 days and one morning dose of 80 mg on Day 28. For cohort 3 it was planned to administer 80 mg placebo b.i.d for 27 days with one morning dose of 80 mg on Day 28. The study was terminated early before completion of cohort 2. | ||
Subject analysis set title |
BN82451B Cohort 1
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients randomised to receive BN82451B in cohort 1 received doses ranging from 40 to 60 mg BN82451B orally b.i.d. for up to 28 days.
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Subject analysis set title |
BN82451B Cohort 2
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients randomised to receive BN82451B in cohort 2 received doses ranging from 60 to 80 mg BN82451B orally b.i.d. for up to 28 days.
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End point title |
Numbers of patients experiencing treatment emergent adverse events (TEAEs). [1] | |||||||||||||||||||||||||||||||||
End point description |
The safety and tolerability of BN82451B versus placebo was determined after oral administration b.i.d. for 28 days in patients with HD. Numbers of patients experiencing TEAEs, including information on seriousness, intensity, drug relationship and those leading to withdrawal are presented for all doses of BN82451B and placebo.
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End point type |
Primary
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End point timeframe |
From Day 1 to end of study
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned and performed for the primary end point, as this was a safety measure in a small study population. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||
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End point title |
Area under the plasma concentration time curve (AUC) | |||||||||||||||||||||||||||||||||||||||
End point description |
The AUC was determined for BN82451B and its metabolites BN2468 and BN7167 within a dosage interval (0-12 hours) on Days 1, and 14 and 28. Day 1 data represent the AUC after the first dose (AUC[0-12]). The data for Days 14 and 28 (AUC[τ,ss]) represent the AUC at steady state at the initial cohort dose and following dose escalation, respectively. Data is presented for cohorts 1 and 2, as the study terminated prior to dosing of cohort 3.
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End point type |
Secondary
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End point timeframe |
0-12 hours on Days 1, 14 and 28
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| Notes [2] - For BN82451B Cohort 2, BN2468 AUC(0-12) was not computed as Cmax (tmax) occurred at 12 hours. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||
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End point title |
Peak plasma concentration (Cmax) | |||||||||||||||||||||||||||||||||||||||
End point description |
Cmax was determined for BN82451B and its metabolites BN2468 and BN7167 on Days 1, 14 and 28. Day 1 data represent the PK after the first dose (Cmax). The data for Days 14 and 28 represent the Cmax at steady state (Cmax,ss) at the initial cohort dose and following dose escalation, respectively. Data is presented for cohorts 1 and 2, as the study terminated prior to dosing of cohort 3.
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End point type |
Secondary
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End point timeframe |
Days 1, 14 and 28
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||
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End point title |
Time to peak plasma concentration (Tmax) | |||||||||||||||||||||||||||||||||||||||
End point description |
Tmax is the empirical time of Cmax and was determined for BN82451B and its metabolites BN2468 and BN7167 on Days 1, 14 and 28. Day 1 data represent the PK after the first dose (Tmax). The data for Days 14 and 28 represent the Tmax at steady state (Tmax,ss) at the initial cohort dose and following dose escalation, respectively. Data is presented for cohorts 1 and 2, as the study terminated prior to dosing of cohort 3.
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End point type |
Secondary
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End point timeframe |
Days 1, 14 and 28
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||
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End point title |
Change from Baseline to Day 28 in the position-index as determined by Choreomotography | ||||||||||||||||||
End point description |
Choreatic (involuntary) movements were assessed using Choreomotography by calculating a position-index and orientation-index. Patients were asked to grasp and lift a device equipped with an electromagnetic sensor, and were asked to hold the device as stable as possible. Three dimensional (3D) changes in position (x, y and z) and orientation (roll, pitch and yaw) were recorded and used to calculate a position-index and an orientation-index. This method provided an objective measure of the involuntary movements. 5 trials of 20 seconds duration were performed with each hand, and the start and end of each trial was signalled by a cueing tone. The mean changes from Baseline to Day 28 in the position-index of the right and left hands are presented as raw data. The statistical analyses present geometric least squares (GLS) mean ratios in the original units.
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End point type |
Secondary
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End point timeframe |
Baseline (Day-1) to Day 28
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Statistical analysis title |
Left hand position-index | ||||||||||||||||||
Statistical analysis description |
The Mixed Effect Model Repeat Measurement (MMRM) analysis was performed on log-transformed data using the restricted maximum likelihood (REML) model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
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Comparison groups |
BN82451B v Placebo
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Number of subjects included in analysis |
14
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.5743 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
1.104
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Confidence interval |
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level |
90% | ||||||||||||||||||
sides |
2-sided
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lower limit |
0.823 | ||||||||||||||||||
upper limit |
1.482 | ||||||||||||||||||
Statistical analysis title |
Right hand position-index | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
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Comparison groups |
BN82451B v Placebo
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Number of subjects included in analysis |
14
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.4349 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
1.141
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Confidence interval |
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level |
90% | ||||||||||||||||||
sides |
2-sided
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lower limit |
0.862 | ||||||||||||||||||
upper limit |
1.51 | ||||||||||||||||||
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End point title |
Change from Baseline to Day 28 in the orientation-index as determined by Choreomotography | ||||||||||||||||||
End point description |
Choreatic (involuntary) movements were assessed using Choreomotography by calculating a position-index and orientation-index. Patients were asked to grasp and lift a device equipped with an electromagnetic sensor, and were asked to hold the device as stable as possible. 3D changes in position (x, y and z) and orientation (roll, pitch and yaw) were recorded and used to calculate a position-index and an orientation-index. This method provided an objective measure of the involuntary movements. 5 trials of 20 seconds duration were performed with each hand, and the start and end of each trial was signalled by a cueing tone. The mean changes from Baseline to Day 28 in the orientation-index of the right and left hands are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
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End point type |
Secondary
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End point timeframe |
Baseline (Day -1) to Day 28
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Statistical analysis title |
Left hand orientation-index | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
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Comparison groups |
BN82451B v Placebo
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Number of subjects included in analysis |
14
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.8937 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
1.035
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Confidence interval |
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level |
90% | ||||||||||||||||||
sides |
2-sided
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lower limit |
0.675 | ||||||||||||||||||
upper limit |
1.587 | ||||||||||||||||||
Statistical analysis title |
Right hand orientation-index | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
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Comparison groups |
BN82451B v Placebo
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Number of subjects included in analysis |
14
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.636 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
1.093
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||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.8 | ||||||||||||||||||
upper limit |
1.493 | ||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean grip force variability as determined by Manumotography | ||||||||||||||||||
End point description |
The coordination of isometric grip forces in the precision grip between the thumb and index finger were assessed by Manumotography. Grip forces were assessed during grip initiation, object transport and in a static holding phase. Subjects were instructed to grasp and lift a device equipped with a force transducer and 3D position sensor in the precision grip between thumb and index finger and hold it stable adjacent to a marker 10 centimetres high. Grip forces and 3D position and orientation of the object were recorded. Mean isometric grip forces and grip force variability in the static phase (expressed as coefficient of variation = standard deviation/mean x 100 [GFV-C]) were calculated during a 15 second period. 5 trials of 20 seconds duration were performed with each hand. The mean changes from Baseline to Day 28 in the grip force variability of each hand are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline (Day -1) to Day 28
|
||||||||||||||||||
|
|||||||||||||||||||
Statistical analysis title |
Left hand grip force variability | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.2865 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
1.247
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.886 | ||||||||||||||||||
upper limit |
1.756 | ||||||||||||||||||
Statistical analysis title |
Right hand grip force variability | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.5338 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
1.16
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.781 | ||||||||||||||||||
upper limit |
1.724 | ||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean isometric grip forces as determined by Manumotography | ||||||||||||||||||
End point description |
The coordination of isometric grip forces in the precision grip between the thumb and index finger were assessed by Manumotography. Grip forces were assessed during grip initiation, object transport and in a static holding phase. Subjects were instructed to grasp and lift a device equipped with a force transducer and 3D position sensor in the precision grip between thumb and index finger and hold it stable adjacent to a marker 10 centimetres high. Grip forces and 3D position and orientation of the object were recorded. Mean isometric grip forces and grip force variability in the static phase (expressed as coefficient of variation = standard deviation/mean x 100 [GFV-C]) were calculated during a 15 second period. 5 trials of 20 seconds duration were performed with each hand. The mean changes from Baseline to Day 28 in the mean isometric grip forces of each hand are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline (Day -1) to Day 28
|
||||||||||||||||||
|
|||||||||||||||||||
Statistical analysis title |
Left hand isometric grip forces | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.0864 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
0.693
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.487 | ||||||||||||||||||
upper limit |
0.985 | ||||||||||||||||||
Statistical analysis title |
Right hand isometric grip forces | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.0399 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
0.686
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.508 | ||||||||||||||||||
upper limit |
0.925 | ||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean duration and variability of inter onset intervals (IOI) as assessed by Digitomotography | ||||||||||||||||||||||||
End point description |
Digitomotography was used to assess the duration and the variability of tap IOI in an index finger speeded tapping task. The patient placed their hand on a hand rest with their index finger positioned on a force transducer, and recordings were started after practice runs. The patient was then instructed to finger tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each hand. The mean changes from Baseline to Day 28 in the duration and variability of IOI for the left and right hands are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline (Day-1) to Day 28
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Left finger IOI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.0574 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.509
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
1.06 | ||||||||||||||||||||||||
upper limit |
2.15 | ||||||||||||||||||||||||
Statistical analysis title |
Right finger IOI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.8277 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
0.953
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.662 | ||||||||||||||||||||||||
upper limit |
1.372 | ||||||||||||||||||||||||
Statistical analysis title |
Left finger IOI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.0162 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.238
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
1.074 | ||||||||||||||||||||||||
upper limit |
1.426 | ||||||||||||||||||||||||
Statistical analysis title |
Right finger IOI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.632 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.038
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.912 | ||||||||||||||||||||||||
upper limit |
1.182 | ||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean duration and variability of tap durations (TD) as assessed by Digitomotography | ||||||||||||||||||||||||
End point description |
Digitomotography was used to assess the duration and the variability of TD in an index finger speeded tapping task. The patient placed their hand on a hand rest with their index finger positioned on a force transducer, and recordings were started after practice runs. The patient was then instructed to finger tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each hand. The mean changes from Baseline to Day 28 in the duration and variability of TD for the left and right hands are presented a raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline (Day -1) to Day 28
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Left finger Variability of TD | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.3005 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.308
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.85 | ||||||||||||||||||||||||
upper limit |
2.014 | ||||||||||||||||||||||||
Statistical analysis title |
Right finger Variability of TD | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.4793 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.177
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.804 | ||||||||||||||||||||||||
upper limit |
1.722 | ||||||||||||||||||||||||
Statistical analysis title |
Left finger Duration of TD | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.2653 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.15
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.934 | ||||||||||||||||||||||||
upper limit |
1.416 | ||||||||||||||||||||||||
Statistical analysis title |
Right finger Duration of TD | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.6777 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.045
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.875 | ||||||||||||||||||||||||
upper limit |
1.248 | ||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean duration and variability of inter peak intervals (IPI) as assessed by Digitomotography | ||||||||||||||||||||||||
End point description |
Digitomotography was used to assess the duration and the variability of tap IPI in an index finger speeded tapping task. The patient placed their hand on a hand rest with their index finger positioned on a force transducer, and recordings were started after practice runs. The patient was then instructed to finger tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each hand. The mean changes from Baseline to Day 28 in the duration and variability of IPI for the left and right hands are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline (Day -1) to Day 28
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Left finger IPI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.0326 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.618
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
1.124 | ||||||||||||||||||||||||
upper limit |
2.331 | ||||||||||||||||||||||||
Statistical analysis title |
Right finger IPI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.6016 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
0.886
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.605 | ||||||||||||||||||||||||
upper limit |
1.299 | ||||||||||||||||||||||||
Statistical analysis title |
Left finger IPI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.0152 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.242
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
1.077 | ||||||||||||||||||||||||
upper limit |
1.433 | ||||||||||||||||||||||||
Statistical analysis title |
Right finger IPI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.6033 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.042
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.915 | ||||||||||||||||||||||||
upper limit |
1.186 | ||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean duration and variability of inter tap intervals (ITI) as assessed by Digitomotography | ||||||||||||||||||||||||
End point description |
Digitomotography was used to assess the duration and the variability of ITI in an index finger speeded tapping task. The patient placed their hand on a hand rest with their index finger positioned on a force transducer, and recordings were started after practice runs. The patient was then instructed to finger tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each hand. The mean changes from Baseline to Day 28 in the duration and variability of ITI for the left and right hands are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline (Day-1) to Day 28
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Left finger ITI Variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.052 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.657
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
1.086 | ||||||||||||||||||||||||
upper limit |
2.529 | ||||||||||||||||||||||||
Statistical analysis title |
Right finger ITI Variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.6978 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
0.916
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.63 | ||||||||||||||||||||||||
upper limit |
1.333 | ||||||||||||||||||||||||
Statistical analysis title |
Left finger ITI Duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.0522 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.298
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
1.043 | ||||||||||||||||||||||||
upper limit |
1.614 | ||||||||||||||||||||||||
Statistical analysis title |
Right finger ITI Duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.9012 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.014
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.837 | ||||||||||||||||||||||||
upper limit |
1.229 | ||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean duration and variability of IOI as assessed by Dysdiadochomotography | ||||||||||||||||||||||||
End point description |
Dysdiadochomotography was used to assess the regularity of hand taps performed when alternating between the palm and dorsal surface of the hand performing a repetitive pronation/supination movement. The force and duration of the hand taps were recorded, with their hand positioned on a force transducer, and recordings were started after practice runs. The patient was then instructed to hand tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each hand. The mean changes from Baseline to Day 28 in the duration and variability of IOI for the left and right hands are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline (Day -1) to Day 28
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Left hand IOI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.6176 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.168
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.697 | ||||||||||||||||||||||||
upper limit |
1.955 | ||||||||||||||||||||||||
Statistical analysis title |
Right hand IOI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.4541 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
0.759
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.411 | ||||||||||||||||||||||||
upper limit |
1.399 | ||||||||||||||||||||||||
Statistical analysis title |
Left hand IOI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.2018 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.119
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.967 | ||||||||||||||||||||||||
upper limit |
1.294 | ||||||||||||||||||||||||
Statistical analysis title |
Right hand IOI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.6527 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.046
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.886 | ||||||||||||||||||||||||
upper limit |
1.234 | ||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean duration and variability of TD as assessed by Dysdiadochomotography | ||||||||||||||||||||||||
End point description |
Dysdiadochomotography was used to assess the regularity of hand taps performed when alternating between the palm and dorsal surface of the hand performing a repetitive pronation/supination movement. The force and duration of the hand taps were recorded, with their hand positioned on a force transducer, and recordings were started after practice runs. The patient was then instructed to hand tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each hand. The mean changes from Baseline to Day 28 in the duration and variability of TD for the left and right hands are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline (Day -1) to Day 28
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Left hand variability of TD | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.8279 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
0.929
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.529 | ||||||||||||||||||||||||
upper limit |
1.63 | ||||||||||||||||||||||||
Statistical analysis title |
Right hand variability of TD | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.2738 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
0.612
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.292 | ||||||||||||||||||||||||
upper limit |
1.283 | ||||||||||||||||||||||||
Statistical analysis title |
Left hand duration of TD | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.9218 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.018
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.752 | ||||||||||||||||||||||||
upper limit |
1.378 | ||||||||||||||||||||||||
Statistical analysis title |
Right hand TD duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.5032 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
0.847
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.561 | ||||||||||||||||||||||||
upper limit |
1.277 | ||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean duration and variability of IPI as assessed by Dysdiadochomotography | ||||||||||||||||||||||||
End point description |
Dysdiadochomotography was used to assess the regularity of hand taps performed when alternating between the palm and dorsal surface of the hand performing a repetitive pronation/supination movement. The force and duration of the hand taps were recorded, with their hand positioned on a force transducer, and recordings were started after practice runs. The patient was then instructed to hand tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each hand. The mean changes from Baseline to Day 28 in the duration and variability of IPI for the left and right hands are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline (Day-1) to Day 28
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Left hand IPI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.6759 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.14
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.677 | ||||||||||||||||||||||||
upper limit |
1.917 | ||||||||||||||||||||||||
Statistical analysis title |
Right hand IPI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.5764 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
0.815
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.444 | ||||||||||||||||||||||||
upper limit |
1.496 | ||||||||||||||||||||||||
Statistical analysis title |
Left hand IPI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.2127 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.115
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.965 | ||||||||||||||||||||||||
upper limit |
1.289 | ||||||||||||||||||||||||
Statistical analysis title |
Right hand IPI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.5661 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.059
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.897 | ||||||||||||||||||||||||
upper limit |
1.25 | ||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean duration and variability of ITI as assessed by Dysdiadochomotography | ||||||||||||||||||||||||
End point description |
Dysdiadochomotography was used to assess the regularity of hand taps performed when alternating between the palm and dorsal surface of the hand performing a repetitive pronation/supination movement. The force and duration of the hand taps were recorded, with their hand positioned on a force transducer, and recordings were started after practice runs. The patient was then instructed to hand tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each hand. The mean changes from Baseline to Day 28 in the duration and variability of ITI for the left and right hands are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline (Day -1) to Day 28
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Left hand ITI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.0874 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.571
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
1.018 | ||||||||||||||||||||||||
upper limit |
2.424 | ||||||||||||||||||||||||
Statistical analysis title |
Right hand ITI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.6431 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.18
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.644 | ||||||||||||||||||||||||
upper limit |
2.162 | ||||||||||||||||||||||||
Statistical analysis title |
Left hand ITI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.0389 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.193
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
1.038 | ||||||||||||||||||||||||
upper limit |
1.371 | ||||||||||||||||||||||||
Statistical analysis title |
Right hand ITI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.1641 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.138
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.976 | ||||||||||||||||||||||||
upper limit |
1.327 | ||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean duration and variability of IOI as assessed by Pedomotography | ||||||||||||||||||||||||
End point description |
Pedomotography was used to assess the tap duration and variability in a foot speeded tapping task. The patient placed their foot on the foot device such that the ball of the foot was positioned above a force transducer, and recordings were started after practice runs. The patient was then instructed to foot tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each foot. The mean changes from Baseline to Day 28 in the duration and variability of IOI for the left and right feet are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline (Day-1) to Day 28
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Left foot IOI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.015 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
2.163
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
1.295 | ||||||||||||||||||||||||
upper limit |
3.614 | ||||||||||||||||||||||||
Statistical analysis title |
Right foot IOI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.5136 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.274
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.688 | ||||||||||||||||||||||||
upper limit |
2.361 | ||||||||||||||||||||||||
Statistical analysis title |
Left foot IOI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.0218 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.56
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
1.139 | ||||||||||||||||||||||||
upper limit |
2.137 | ||||||||||||||||||||||||
Statistical analysis title |
Right foot IOI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.372 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.251
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.825 | ||||||||||||||||||||||||
upper limit |
1.899 | ||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean duration and variability of TD as assessed by Pedomotography | ||||||||||||||||||||||||
End point description |
Pedomotography was used to assess the tap duration and variability in a foot speeded tapping task. The patient placed their foot on the foot device such that the ball of the foot was positioned above a force transducer, and recordings were started after practice runs. The patient was then instructed to foot tap as fast as possible between 2 auditory cues. The patient was then instructed to foot tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each foot. The mean changes from Baseline to Day 28 in the duration and variability of TD for the left and right feet are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline (Day-1) to Day 28
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Left foot TD variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.915 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.911
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
1.017 | ||||||||||||||||||||||||
upper limit |
3.592 | ||||||||||||||||||||||||
Statistical analysis title |
Right foot TD variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.2745 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.687
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.762 | ||||||||||||||||||||||||
upper limit |
3.737 | ||||||||||||||||||||||||
Statistical analysis title |
Left foot TD duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.1148 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.598
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.98 | ||||||||||||||||||||||||
upper limit |
2.608 | ||||||||||||||||||||||||
Statistical analysis title |
Right foot TD duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.308 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.454
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.789 | ||||||||||||||||||||||||
upper limit |
2.679 | ||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean duration and variability of IPI as assessed by Pedomotography | ||||||||||||||||||||||||
End point description |
Pedomotography was used to assess the tap duration and variability in a foot speeded tapping task. The patient placed their foot on the foot device such that the ball of the foot was positioned above a force transducer, and recordings were started after practice runs. The patient was then instructed to foot tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each foot. The mean changes from Baseline to Day 28 in the duration and variability of IPI for the left and right feet are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline (Day-1) to Day 28
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Left foot IPI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.0079 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
2.272
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
1.381 | ||||||||||||||||||||||||
upper limit |
3.737 | ||||||||||||||||||||||||
Statistical analysis title |
Right foot IPI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.0204 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.21
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.686 | ||||||||||||||||||||||||
upper limit |
2.133 | ||||||||||||||||||||||||
Statistical analysis title |
Left foot IPI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.0204 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.564
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
1.144 | ||||||||||||||||||||||||
upper limit |
2.138 | ||||||||||||||||||||||||
Statistical analysis title |
Right foot IPI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.3144 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.269
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.856 | ||||||||||||||||||||||||
upper limit |
1.884 | ||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean duration and variability of ITI as assessed by Pedomotography | ||||||||||||||||||||||||
End point description |
Pedomotography was used to assess the tap duration and variability in a foot speeded tapping task. The patient placed their foot on the foot device such that the ball of the foot was positioned above a force transducer, and recordings were started after practice runs. The patient was then instructed to foot tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each foot. The mean changes from Baseline to Day 28 in the duration and variability of ITI for the left and right feet are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline (Day-1) to Day 28
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Left foot ITI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.0324 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.914
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
1.167 | ||||||||||||||||||||||||
upper limit |
3.141 | ||||||||||||||||||||||||
Statistical analysis title |
Right foot ITI variability | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.246 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.462
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.85 | ||||||||||||||||||||||||
upper limit |
2.515 | ||||||||||||||||||||||||
Statistical analysis title |
Left foot ITI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.1057 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.387
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.994 | ||||||||||||||||||||||||
upper limit |
1.935 | ||||||||||||||||||||||||
Statistical analysis title |
Right foot ITI duration | ||||||||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.7342 | ||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||||||||
Point estimate |
1.074
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
0.758 | ||||||||||||||||||||||||
upper limit |
1.523 | ||||||||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean variability of peak tapping forces (TF) as assessed by Digitomotography | ||||||||||||||||||
End point description |
Digitomotography was used to assess the duration and the variability of TD in an index finger speeded tapping task. The patient placed their hand on a hand rest with their index finger positioned on a force transducer, and recordings were started after practice runs. The patient was then instructed to finger tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each hand. The mean changes from Baseline to Day 28 in the variability of TF for the left and right hands are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline (Day-1) to Day 28
|
||||||||||||||||||
|
|||||||||||||||||||
Statistical analysis title |
Left finger TF variability | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.1779 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
1.198
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.96 | ||||||||||||||||||
upper limit |
1.494 | ||||||||||||||||||
Statistical analysis title |
Right finger TF variability | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.8036 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
0.966
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.765 | ||||||||||||||||||
upper limit |
1.22 | ||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean tapping frequency (freq) as assessed by Digitomotography | ||||||||||||||||||
End point description |
Digitomotography was used to assess the duration and the variability of TD in an index finger speeded tapping task. The patient placed their hand on a hand rest with their index finger positioned on a force transducer, and recordings were started after practice runs. The patient was then instructed to finger tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each hand. The tapping frequency was calculated as the number of taps between the onsets of the first and the last tap divided by the time in between. The mean changes from Baseline to Day 28 in the tapping frequency for the left and right hands are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline (Day-1) to Day 28
|
||||||||||||||||||
|
|||||||||||||||||||
Statistical analysis title |
Left finger freq | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.0177 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
0.812
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.706 | ||||||||||||||||||
upper limit |
0.935 | ||||||||||||||||||
Statistical analysis title |
Right finger freq | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.6491 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
0.967
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.856 | ||||||||||||||||||
upper limit |
1.093 | ||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean variability of peak TF as assessed by Dysdiadochomotography | ||||||||||||||||||
End point description |
Dysdiadochomotography was used to assess the regularity of hand taps performed when alternating between the palm and dorsal surface of the hand performing a repetitive pronation/supination movement. The force and duration of the hand taps were recorded, with their hand positioned on a force transducer, and recordings were started after practice runs. The patient was then instructed to hand tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each hand. The mean changes from Baseline to Day 28 in the variability of TF for the left and right hands are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline (Day-1) to Day 28
|
||||||||||||||||||
|
|||||||||||||||||||
Statistical analysis title |
Left hand TF variability | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.5668 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
0.93
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.755 | ||||||||||||||||||
upper limit |
1.147 | ||||||||||||||||||
Statistical analysis title |
Right hand TF variability | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.8686 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
0.978
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.778 | ||||||||||||||||||
upper limit |
1.229 | ||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean tapping frequency as assessed by Dysdiadochomotography | ||||||||||||||||||
End point description |
Dysdiadochomotography was used to assess the regularity of hand taps performed when alternating between the palm and dorsal surface of the hand performing a repetitive pronation/supination movement. The force and duration of the hand taps were recorded, with their hand positioned on a force transducer, and recordings were started after practice runs. The patient was then instructed to hand tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each hand. The tapping frequency was calculated as the number of taps between the onsets of the first and the last tap divided by the time in between. The mean changes from Baseline to Day 28 in the tapping frequency for the left and right hands are presented as raw data. GLS mean ratios are in original units.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline (Day -1) to Day 28
|
||||||||||||||||||
|
|||||||||||||||||||
Statistical analysis title |
Left hand freq | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.1244 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
0.879
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.765 | ||||||||||||||||||
upper limit |
1.009 | ||||||||||||||||||
Statistical analysis title |
Right hand freq | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||
Number of subjects included in analysis |
14
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.3535 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
0.919
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.789 | ||||||||||||||||||
upper limit |
1.069 | ||||||||||||||||||
|
|||||||||||||||||||
End point title |
Change from Baseline to Day 28 in the mean variability of peak TF as assessed by Pedomotography | ||||||||||||||||||
End point description |
Pedomotography was used to assess the tap duration and variability in a foot speeded tapping task. The patient placed their foot on the foot device such that the ball of the foot was positioned above a force transducer, and recordings were started after practice runs. The patient was then instructed to foot tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each foot. The mean changes from Baseline to Day 28 in the variability of TF for the left and right feet are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline (Day -1) to Day 28
|
||||||||||||||||||
|
|||||||||||||||||||
Statistical analysis title |
Left foot TF variability | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.1027 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
1.392
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
0.997 | ||||||||||||||||||
upper limit |
1.943 | ||||||||||||||||||
Statistical analysis title |
Right foot TF variability | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
|
||||||||||||||||||
Comparison groups |
BN82451B v Placebo
|
||||||||||||||||||
Number of subjects included in analysis |
13
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.4494 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
1.158
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
90% | ||||||||||||||||||
sides |
2-sided
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lower limit |
0.84 | ||||||||||||||||||
upper limit |
1.595 | ||||||||||||||||||
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End point title |
Change from Baseline to Day 28 in the mean tapping frequency as assessed by Pedomotography | ||||||||||||||||||
End point description |
Pedomotography was used to assess the tap duration and variability in a foot speeded tapping task. The patient placed their foot on the foot device such that the ball of the foot was positioned above a force transducer, and recordings were started after practice runs. The patient was then instructed to foot tap as fast as possible between 2 auditory cues. The beginning of a tap was defined as a rise of the force by 0.05 N above maximal baseline level. The tap ended when it dropped to 0.05 N before the maximal baseline level was reached again. 5 trials of 10 seconds duration were performed with each foot. The tapping frequency was calculated as the number of taps between the onsets of the first and the last tap divided by the time in between. The mean changes from Baseline to Day 28 in the tapping frequency for the left and right hands are presented as raw data. The statistical analyses present GLS mean ratios in the original units.
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End point type |
Secondary
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End point timeframe |
Baseline (Day -1) to Day 28
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Statistical analysis title |
Left foot freq | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
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Comparison groups |
BN82451B v Placebo
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Number of subjects included in analysis |
13
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.035 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
0.699
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Confidence interval |
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level |
90% | ||||||||||||||||||
sides |
2-sided
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lower limit |
0.53 | ||||||||||||||||||
upper limit |
0.922 | ||||||||||||||||||
Statistical analysis title |
Right foot freq | ||||||||||||||||||
Statistical analysis description |
The MMRM analysis was performed on log-transformed data using the REML model including fixed categorical effects of treatment/cohort group, visit and treatment/cohort by visit interaction as well as the continuous fixed covariate of baseline value. Cohort was fitted as random effect.
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Comparison groups |
BN82451B v Placebo
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Number of subjects included in analysis |
13
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.3556 | ||||||||||||||||||
Method |
MMRM | ||||||||||||||||||
Parameter type |
GLS mean ratio | ||||||||||||||||||
Point estimate |
0.853
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Confidence interval |
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level |
90% | ||||||||||||||||||
sides |
2-sided
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lower limit |
0.64 | ||||||||||||||||||
upper limit |
1.136 | ||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From Day 1 to the end of study visit (a period of up to 7 weeks, consisting of up to 28 days of treatment and up to 3 weeks follow up).
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Adverse event reporting additional description |
AE data is reported as TEAEs.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Patients were randomised to receive oral placebo b.i.d. from Day 1 to Day 27, under double-blinded conditions. On Day 28 only one morning dose of placebo was administered. It was planned for patients to be assigned to 3 cohorts to receive 3 dose levels ranging between 40 and 80 mg b.i.d. For cohort 1, 40 mg placebo b.i.d. was administered during the first 14 days. If this dose was well tolerated then it was increased to 60 mg b.i.d. for 13 days and one morning dose of 60 mg on Day 28. For cohort 2, 60 mg placebo b.i.d. was administered during the first 14 days. If 60 mg b.i.d was well tolerated then it was increased to 80 mg b.i.d. for 13 days and one morning dose of 80 mg on Day 28. For cohort 3 it was planned to administer 80 mg placebo b.i.d for 27 days with one morning dose of 80 mg on Day 28. The study was terminated early before completion of cohort 2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
BN82451B
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Reporting group description |
Patients were randomised to receive oral study medication, BN82451B, b.i.d. from Day 1 to Day 27, under double-blinded conditions. On Day 28 only one morning dose of BN82451B was administered. It was planned for patients to be assigned to 3 cohorts to receive 3 dose levels ranging between 40 and 80 milligrams (mg) b.i.d. For cohort 1, 40 mg BN82451B b.i.d. was administered during the first 14 days. If this dose was well tolerated then it was increased to 60 mg b.i.d. for 13 days and one morning dose of 60 mg on Day 28. For cohort 2, 60 mg BN82451B b.i.d. was administered during the first 14 days. If 60 mg b.i.d was well tolerated then it was increased to 80 mg b.i.d. for 13 days and one morning dose of 80 mg on Day 28. For cohort 3 it was planned to administer 80 mg BN82451B b.i.d for 27 days with one morning dose of 80 mg on Day 28. The study was terminated early before completion of cohort 2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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22 Dec 2014 |
Change in exclusion criteria to exclude subjects with alanine aminotransferase or aspartate aminotransferase values ≥2x upper limit of normal (ULN) or both Gamma Glutamyl Transferase (GGT) and alkaline phosphatase values >3xULN.
Removal of early study termination/subject withdrawal criteria of GGT >3xULN for 2 repeated observations.
Change in criteria related to dose escalation related to clinically significant laboratory abnormalities to remove criterion of GGT >2xULN and include criterion of bilirubin >2xULN. |
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12 Nov 2015 |
Change in inclusion criteria to include subjects aged ≥20 to ≤70 years.
Extension of study duration to approximately 2 years.
Administrative changes (Sponsor's medically responsible person and pharmacovigilance/emergency contact updates). |
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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. | |||
| The study was terminated prematurely due to subject recruitment problems before the completion of cohort 2. | |||
