Study Exploring Safety, Pharmacokinetic and Pharmacodynamic of BN82451 in Male Huntington's Disease Patients

• Sponsor: Ipsen (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02231580
• Collaborator: (none)
• Enrollment: 17
• Location: 1
• Arms: 2
• Actual Duration (Months): 19
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of BN82451B versus placebo after oral administration twice daily (bid) for 28 days in patients with Huntington's Disease (HD).

Condition or Disease	Intervention/Treatment	Phase
Huntington's Disease	Drug: BN82451B; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Sep 1, 2014
• Actual Primary Completion Date: Mar 31, 2016
• Actual Study Completion Date: Mar 31, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BN82451B BN82451B capsule: Up to 3 dose levels (40, 60 or 80 mg) twice daily administered orally.	Drug: BN82451B; BN82451B capsule
Placebo Comparator: Placebo Placebo capsule: Up to 3 dose levels (40, 60 or 80 mg) twice daily administered orally.	Drug: Placebo; Placebo capsule

Outcome Measures

Primary Outcome Measures

1. Numbers of Patients Experiencing Treatment Emergent Adverse Events (TEAEs). [From Day 1 to end of study (a period of up to 7 weeks).]

   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.

Secondary Outcome Measures

1. Area Under the Plasma Concentration Time Curve (AUC) [0-12 hours on Days 1, 14 and 28]

   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.

2. Peak Plasma Concentration (Cmax) [Days 1, 14 and 28]

   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.

3. Time to Peak Plasma Concentration (Tmax) [Days 1, 14 and 28]

   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.

4. Change From Baseline to Day 28 in the Position-index as Determined by Choreomotography [Baseline (Day-1) to Day 28]

   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.

5. Change From Baseline to Day 28 in the Orientation-index as Determined by Choreomotography [Baseline (Day -1) to Day 28]

   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.

6. Change From Baseline to Day 28 in the Mean Grip Force Variability as Determined by Manumotography [Baseline (Day -1) to Day 28]

   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.

7. Change From Baseline to Day 28 in the Mean Isometric Grip Forces as Determined by Manumotography [Baseline (Day -1) to Day 28]

   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.

8. Change From Baseline to Day 28 in the Mean Duration and Variability of Inter Onset Intervals (IOI) as Assessed by Digitomotography [Baseline (Day-1) to Day 28]

   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.

9. Change From Baseline to Day 28 in the Mean Duration and Variability of Tap Durations (TD) as Assessed by Digitomotography [Baseline (Day -1) to Day 28]

   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.

10. Change From Baseline to Day 28 in the Mean Duration and Variability of Inter Peak Intervals (IPI) as Assessed by Digitomotography [Baseline (Day -1) to Day 28]

    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.

11. Change From Baseline to Day 28 in the Mean Duration and Variability of Inter Tap Intervals (ITI) as Assessed by Digitomotography [Baseline (Day-1) to Day 28]

    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.

12. Change From Baseline to Day 28 in the Mean Variability of Peak Tapping Forces (TF) as Assessed by Digitomotography [Baseline (Day-1) to Day 28]

    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.

13. Change From Baseline to Day 28 in the Mean Tapping Frequency (Freq) as Assessed by Digitomotography [Baseline (Day-1) to Day 28]

    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.

14. Change From Baseline to Day 28 in the Mean Duration and Variability of IOI as Assessed by Dysdiadochomotography [Baseline (Day -1) to Day 28]

    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.

15. Change From Baseline to Day 28 in the Mean Duration and Variability of TD as Assessed by Dysdiadochomotography [Baseline (Day -1) to Day 28]

    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.

16. Change From Baseline to Day 28 in the Mean Duration and Variability of IPI as Assessed by Dysdiadochomotography [Baseline (Day-1) to Day 28]

    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.

17. Change From Baseline to Day 28 in the Mean Duration and Variability of ITI as Assessed by Dysdiadochomotography [Baseline (Day -1) to Day 28]

    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.

18. Change From Baseline to Day 28 in the Mean Variability of Peak TF as Assessed by Dysdiadochomotography [Baseline (Day-1) to Day 28]

    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.

19. Change From Baseline to Day 28 in the Mean Tapping Frequency as Assessed by Dysdiadochomotography [Baseline (Day -1) to Day 28]

    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.

20. Change From Baseline to Day 28 in the Mean Duration and Variability of IOI as Assessed by Pedomotography [Baseline (Day-1) to Day 28]

    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.

21. Change From Baseline to Day 28 in the Mean Duration and Variability of TD as Assessed by Pedomotography [Baseline (Day-1) to Day 28]

    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.

22. Change From Baseline to Day 28 in the Mean Duration and Variability of IPI as Assessed by Pedomotography [Baseline (Day-1) to Day 28]

    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.

23. Change From Baseline to Day 28 in the Mean Duration and Variability of ITI as Assessed by Pedomotography [Baseline (Day-1) to Day 28]

    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.

24. Change From Baseline to Day 28 in the Mean Variability of Peak TF as Assessed by Pedomotography [Baseline (Day -1) to Day 28]

    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.

25. Change From Baseline to Day 28 in the Mean Tapping Frequency as Assessed by Pedomotography [Baseline (Day -1) to Day 28]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 70 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male subjects 20 to 70 years old (inclusive).

• Provision of written informed consent prior to any study related procedures. In this study consent may be provided by the legal guardian or carer.

• Confirmed symptomatic Huntington's Disease diagnosed based on clinical features (i.e. Diagnostic Confidence Level equal to 4) and presence of at least 36 cytosine adenine guanine (CAG) repeats in the Huntington gene as documented by a copy of a previous genetic test report.

• Unified Huntington's Disease Rated Scale-Total Motor Score (UDHRS-TMS) greater than or equal to 15.

• Ambulatory.

• UDHRS-Total Functional Capacity (TFC) greater than or equal to 3 (i.e. Shoulson & Fahn Scale stages 1-3 inclusive.

• Subjects on antipsychotic, antidepressant, anxiolytic and hypnotic therapy must have been on stable treatment 4 weeks prior to study drug start and during the study period.

• Able to swallow study medication.

• Able to perform Q-Motor tests.

• If his partner is at risk of pregnancy, the subject agrees to use a condom or be abstinent for 14 days after the last intake of study drug.

Exclusion Criteria:

• Juvenile forms of Huntington's Disease.

• Any form of chorea other than Huntington's Disease.

• History of seizure, epilepsy or other convulsive disorder, with the exception of febrile seizures in childhood.

• History of conditions susceptible to induce seizures such as severe traumatic brain injury, brain tumours, stroke.

• History of neurosurgical procedure.

• Current evidence or history (within 1 year of Baseline) of psychosis, hallucinations or delusions, including major depression with psychotic features, as defined in the Diagnostic and Statistical Manual, Fourth Edition, Text Revision (DSM-IV-TR). Patients currently experiencing mild depression, or moderate depression which is adequately and appropriately treated in the judgement of the investigator, can participate if depression is not expected to interfere with study participation.

• History of drug and/or alcohol abuse as per the DSM IV-TR criteria within 12 months prior to Baseline.

• At imminent risk of self harm based on investigator's clinical judgment, with a "yes" answer on item 4 or 5 on the Columbia-Suicide Severity Rating Scale (CSSRS) questionnaire.

• Mini Mental State Exam (MMSE) total score less than or equal to 23.

• Used any investigational drugs within 30 days prior to Screening or 5 half lives, whichever is the longest.

• Known allergy/sensitivity to the study drugs or their excipients.

• A severe or ongoing unstable medical condition (e.g. cardiac, hepatic, renal, metabolic or endocrine).

• Any clinically significant condition which, in the opinion of the investigator, would interfere with the trial evaluations or optimal participation in the trial.

• Any significant laboratory results which, in the investigator's opinion, would not be compatible with study participation or represent a risk for subjects while in the study.

• History of malignant disease within the 5 years prior to Screening (with the exception of basal cell and squamous cell carcinomas of the skin that have been completely excised, in situ prostate cancer with a normal prostate specific antigen).

• An estimated Creatinine Clearance (CrCl) of less than 60 mL/minute (using the Cockcroft-Gault formula).

• Alanine Aminotransferase (ALT)/Aspartate Aminotransferase (AST) values greater than or equal to 2 times the Upper Limit of Normal range (ULN) or both GGT and ALT values greater than three times the ULN.

• Known history of hepatitis B or C or Human Immunodeficiency Virus (HIV) or positive serology at Screening.

• Corrected QT interval using Bazett's correction (QTcB) greater than 450 ms or other clinically significant ECG findings.

• Receiving tetrabenazine within 4 weeks prior to Baseline.

• Taking the following prohibited medications/substances: Strong Cytochrome (CYP) 3A4 inhibitors and Strong CYP3A4 inducers (Wash out prior to Baseline 30 days or 5 half lives,whichever is the longest), CYP2B6 substrates, CYP1A2 substrates, CYP3A4 substrates, CYP2C19 substrates (assessed on a case by case basis)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Monchengladbach		Germany

Sponsors and Collaborators

• Ipsen

Investigators

• Study Director: Ipsen Medical Director, Ipsen

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ipsen
• ClinicalTrials.gov Identifier: NCT02231580
• Other Study ID Numbers: 8-55-52966-005; 2013-002899-41
• First Posted: Sep 4, 2014
• Last Update Posted: Jan 15, 2019
• Last Verified: Jan 1, 2019

• Keywords provided by Ipsen: Neurodegenerative genetic disorder
• Additional relevant MeSH terms: Huntington Disease

Study Results

Participant Flow

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.
Pre-assignment Detail	Male patients 20-70 years with a documented diagnosis of Huntington's Disease (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.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Period Title: Overall Study
STARTED	14	3
Cohort 1	8	2
Cohort 2	6	1
COMPLETED	9	3
NOT COMPLETED	5	0

Baseline Characteristics

Arm/Group Title	BN82451B	Placebo	Total Title
Arm/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.	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.
Overall Participants	14	3	17
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.6 (14.4)	50.0 (8.7)	46.6 (14.4)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	14 100%	3 100%	17 100%

Outcome Measures

1. Primary Outcome

Title	Numbers of Patients Experiencing Treatment Emergent Adverse Events (TEAEs).
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.
Time Frame	From Day 1 to end of study (a period of up to 7 weeks).

Outcome Measure Data

Analysis Population Description

The Safety Population consisted of all randomised patients who received at least one dose of study medication.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	14	3
Patients with any TEAEs	11 78.6%	2 66.7%
Patients with any serious TEAE	0 0%	0 0%
Patients with at least 1 severe TEAE	0 0%	0 0%
Patients with at least 1 moderate TEAE	8 57.1%	1 33.3%
Patients with at least 1 mild TEAE	11 78.6%	1 33.3%
Patients with TEAEs related to study medication	9 64.3%	0 0%
Patients with TEAEs leading to withdrawal	5 35.7%	0 0%
Patients with any TEAEs leading to death	0 0%	0 0%

2. Secondary Outcome

Title	Area Under the Plasma Concentration Time Curve (AUC)
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.
Time Frame	0-12 hours on Days 1, 14 and 28

Outcome Measure Data

Analysis Population Description

The PK population consisted of all subjects from the safety population who had no major protocol deviations affecting the PK variables and who had a sufficient number of plasma BN82451B concentrations to estimate the main PK parameters.

Arm/Group Title	BN82451B Cohort 1	BN82451B Cohort 2
Arm/Group 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.	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.
Measure Participants	8	6
Day 1 BN82451B AUC(0-12)	512.93 (112.53)	783.78 (144.45)
Day 1 BN2468 AUC(0-12)	90.66 (40.68)
Day 1 BN7167 AUC(0-12)	16.82 (9.01)	31.67 (24.63)
Day 14 BN82451B AUCτ,ss	1521.11 (593.22)	2594.05 (1077.08)
Day 14 BN2468 AUC(τ,ss)	735.51 (203.91)	1531.00 (412.43)
Day 14 BN7167 AUC(τ,ss)	33.39 (20.08)	46.73 (36.76)
Day 28 BN82451B AUC(τ,ss)	2357.95 (977.74)	3313.45 (1517.6)
Day 28 BN2468 AUC(τ,ss)	1509.67 (105.94)	1936.35 (569.97)
Day 28 BN7167 AUC(τ,ss)	34.64 (16.05)	63.81 (57.70)

3. Secondary Outcome

Title	Peak Plasma Concentration (Cmax)
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.
Time Frame	Days 1, 14 and 28

Outcome Measure Data

Analysis Population Description

The PK population consisted of all subjects from the safety population who had no major protocol deviations affecting the PK variables and who had a sufficient number of plasma BN82451B concentrations to estimate the main PK parameters.

Arm/Group Title	BN82451B Cohort 1	BN82451B Cohort 2
Arm/Group 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.	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.
Measure Participants	8	6
Day 1 BN82451B Cmax	71.61 (14.81)	101.45 (16.25)
Day 1 BN2468 Cmax	9.03 (4.14)	18.87 (13.00)
Day 1 BN7167 Cmax	3.62 (1.62)	5.61 (3.62)
Day 14 BN82451B Cmax,ss	162.88 (56.31)	271.64 (99.90)
Day 14 BN2468 Cmax,ss	75.34 (15.16)	125.34 (38.13)
Day 14 BN7167 Cmax,ss	4.90 (2.35)	6.28 (3.55)
Day 28 BN82451B Cmax,ss	251.77 (105.64)	340.41 (156.61)
Day 28 BN2468 Cmax,ss	135.19 (5.06)	171.64 (47.64)
Day 28 BN 7167 Cmax,ss	5.51 (1.82)	9.54 (6.92)

4. Secondary Outcome

Title	Time to Peak Plasma Concentration (Tmax)
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.
Time Frame	Days 1, 14 and 28

Outcome Measure Data

Analysis Population Description

The PK population consisted of all subjects from the safety population who had no major protocol deviations affecting the PK variables and who had a sufficient number of plasma BN82451B concentrations to estimate the main PK parameters.

Arm/Group Title	BN82451B Cohort 1	BN82451B Cohort 2
Arm/Group 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.	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.
Measure Participants	8	6
Day 1 BN82451B Tmax	3.0	2.51
Day 1 BN2468 Tmax	9.98	11.92
Day 1 BN7167 Tmax	1.00	1.00
Day 14 BN82451B Tmax,ss	3.0	3.0
Day 14 BN2468 Tmax,ss	4	2.51
Day 14 BN7167 Tmax,ss	1	1
Day 28 BN82451B Tmax,ss	3	2.56
Day 28 BN2468 Tmax,ss	4.06	2.06
Day 28 BN7167 Tmax,ss	1	1.52

5. Secondary Outcome

Title	Change From Baseline to Day 28 in the Position-index as Determined by Choreomotography
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.
Time Frame	Baseline (Day-1) to Day 28

Outcome Measure Data

Analysis Population Description

The Pharmacodynamic (PD) population consisted of all subjects from the safety population who have not reported major protocol violations impacting quantitative measures of motor function (Q-motor) evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left hand position-index	0.021 (0.024)	0.009 (0.007)
Right hand position-index	0.018 (0.014)	0.009 (0.006)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left hand position-index statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.5743
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.104
	Confidence Interval	(2-Sided) 90%; 0.823 to 1.482
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right hand position-index statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.4349
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.141
	Confidence Interval	(2-Sided) 90%; 0.862 to 1.510
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline to Day 28 in the Orientation-index as Determined by Choreomotography
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.
Time Frame	Baseline (Day -1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left hand orientation-index	0.131 (0.125)	0.082 (0.100)
Right hand orientation-index	0.098 (0.087)	0.054 (0.045)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left hand orientation-index statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.8937
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.035
	Confidence Interval	(2-Sided) 90%; 0.675 to 1.587
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right hand orientation-index statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.6360
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.093
	Confidence Interval	(2-Sided) 90%; 0.800 to 1.493
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Grip Force Variability as Determined by Manumotography
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.
Time Frame	Baseline (Day -1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left hand grip force variability	5.74 (4.38)	2.61 (4.57)
Right hand grip force variability	5.82 (7.94)	2.35 (1.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left hand grip force variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.2865
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.247
	Confidence Interval	(2-Sided) 90%; 0.886 to 1.756
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right hand grip force variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.5338
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.160
	Confidence Interval	(2-Sided) 90%; 0.781 to 1.724
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Isometric Grip Forces as Determined by Manumotography
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.
Time Frame	Baseline (Day -1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left hand isometric grip forces	-0.75 (2.86)	1.55 (1.99)
Right hand isometric grip forces	-2.06 (6.00)	0.91 (1.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left hand isometric grip forces statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0864
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.693
	Confidence Interval	(2-Sided) 90%; 0.487 to 0.985
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right hand isometric grip forces statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0399
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.686
	Confidence Interval	(2-Sided) 90%; 0.508 to 0.925
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Duration and Variability of Inter Onset Intervals (IOI) as Assessed by Digitomotography
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.
Time Frame	Baseline (Day-1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left finger IOI variability	0.039 (0.048)	-0.009 (0.002)
Right finger IOI variability	0.057 (0.062)	0.038 (0.049)
Left finger IOI duration	0.088 (0.075)	-0.015 (0.041)
Right finger IOI duration	0.069 (0.059)	0.032 (0.031)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left finger IOI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0574
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.509
	Confidence Interval	(2-Sided) 90%; 1.060 to 2.150
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right finger IOI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.8277
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.953
	Confidence Interval	(2-Sided) 90%; 0.662 to 1.372
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left finger IOI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0162
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.238
	Confidence Interval	(2-Sided) 90%; 1.074 to 1.426
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right finger IOI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.6320
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.038
	Confidence Interval	(2-Sided) 90%; 0.912 to 1.182
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Duration and Variability of Tap Durations (TD) as Assessed by Digitomotography
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.
Time Frame	Baseline (Day -1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left finger Variability of TD	0.007 (0.024)	-0.007 (0.015)
Right finger Variability of TD	0.017 (0.016)	0.012 (0.017)
Left finger Duration of TD	0.010 (0.021)	-0.011 (0.039)
Right finger Duration of TD	0.012 (0.021)	0.001 (0.025)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left finger variability of TD statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.3005
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.308
	Confidence Interval	(2-Sided) 90%; 0.85 to 2.014
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right finger variability of TD statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.4793
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.177
	Confidence Interval	(2-Sided) 90%; 0.804 to 1.722
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left finger duration of TD statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.2653
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.150
	Confidence Interval	(2-Sided) 90%; 0.934 to 1.416
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right finger duration of TD statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.6777
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.045
	Confidence Interval	(2-Sided) 90%; 0.875 to 1.248
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Duration and Variability of Inter Peak Intervals (IPI) as Assessed by Digitomotography
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.
Time Frame	Baseline (Day -1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left finger IPI variability	0.040 (0.049)	-0.009 (0.007)
Right finger IPI variability	0.057 (0.067)	0.038 (0.044)
Left finger IPI duration	0.088 (0.076)	-0.017 (0.042)
Right finger IPI duration	0.069 (0.059)	0.031 (0.030)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left finger IPI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0326
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.618
	Confidence Interval	(2-Sided) 90%; 1.124 to 2.331
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right finger IPI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.6016
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.886
	Confidence Interval	(2-Sided) 90%; 0.605 to 1.299
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left finger IPI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0152
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.242
	Confidence Interval	(2-Sided) 90%; 1.077 to 1.433
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right finger IPI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.6033
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.042
	Confidence Interval	(2-Sided) 90%; 0.915 to 1.186
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Duration and Variability of Inter Tap Intervals (ITI) as Assessed by Digitomotography
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.
Time Frame	Baseline (Day-1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left finger ITI Variability	0.041 (0.05)	-0.007 (0.01)
Right finger ITI Variability	0.053 (0.068)	0.03 (0.034)
Left finger ITI Duration	0.078 (0.076)	-0.005 (0.006)
Right finger ITI Duration	0.056 (0.048)	0.03 (0.046)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left finger ITI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0520
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.657
	Confidence Interval	(2-Sided) 90%; 1.086 to 2.529
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right finger ITI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.6978
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.916
	Confidence Interval	(2-Sided) 90%; 0.630 to 1.333
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left finger ITI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0522
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.298
	Confidence Interval	(2-Sided) 90%; 1.043 to 1.614
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right finger ITI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.9012
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.014
	Confidence Interval	(2-Sided) 90%; 0.837 to 1.229
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Variability of Peak Tapping Forces (TF) as Assessed by Digitomotography
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.
Time Frame	Baseline (Day-1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left finger TF	0.65 (6.97)	-6.43 (6.26)
Right finger TF	3.75 (12.86)	-0.11 (8.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left finger TF statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.1779
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.198
	Confidence Interval	(2-Sided) 90%; 0.96 to 1.494
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right finger TF statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.8036
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.966
	Confidence Interval	(2-Sided) 90%; 0.765 to 1.220
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Tapping Frequency (Freq) as Assessed by Digitomotography
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.
Time Frame	Baseline (Day-1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left finger freq	-0.492 (0.382)	-0.001 (0.315)
Right finger freq	-0.466 (0.389)	-0.365 (0.231)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left finger freq statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0177
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.812
	Confidence Interval	(2-Sided) 90%; 0.706 to 0.935
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right finger freq statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.6491
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.967
	Confidence Interval	(2-Sided) 90%; 0.856 to 1.093
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Duration and Variability of IOI as Assessed by Dysdiadochomotography
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.
Time Frame	Baseline (Day -1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left hand IOI variability	0.032 (0.135)	0.036 (0.023)
Right hand IOI variability	0.031 (0.094)	0.163 (0.276)
Left hand IOI duration	0.054 (0.114)	0.028 (0.043)
Right hand IOI duration	0.074 (0.101)	0.074 (0.132)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left hand IOI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.6176
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.168
	Confidence Interval	(2-Sided) 90%; 0.697 to 1.955
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right hand IOI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.4541
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.759
	Confidence Interval	(2-Sided) 90%; 0.411 to 1.399
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left hand IOI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.2018
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.119
	Confidence Interval	(2-Sided) 90%; 0.967 to 1.294
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right hand IOI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.6527
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.046
	Confidence Interval	(2-Sided) 90%; 0.886 to 1.234
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Duration and Variability of TD as Assessed by Dysdiadochomotography
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.
Time Frame	Baseline (Day -1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left hand variability of TD	0.001 (0.138)	0.023 (0.026)
Right hand variability of TD	-0.012 (0.073)	0.078 (0.128)
Left hand duration of TD	-0.006 (0.088)	0.017 (0.027)
Right hand duration of TD	-0.019 (0.089)	0.022 (0.069)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left hand variability of TD statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.8279
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.929
	Confidence Interval	(2-Sided) 90%; 0.529 to 1.630
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right hand variability of TD statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.2738
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.612
	Confidence Interval	(2-Sided) 90%; 0.292 to 1.283
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left hand duration of TD statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.9218
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.018
	Confidence Interval	(2-Sided) 90%; 0.752 to 1.378
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right hand duration of TD statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.5032
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.847
	Confidence Interval	(2-Sided) 90%; 0.561 to 1.277
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Duration and Variability of IPI as Assessed by Dysdiadochomotography
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.
Time Frame	Baseline (Day-1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left hand IPI variability	0.045 (0.124)	0.049 (0.046)
Right hand IPI variability	0.027 (0.07)	0.131 (0.219)
Left hand IPI duration	0.057 (0.109)	0.029 (0.04)
Right hand IPI duration	0.079 (0.105)	0.066 (0.118)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left hand IPI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.6759
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.140
	Confidence Interval	(2-Sided) 90%; 0.677 to 1.917
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right hand IPI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.5764
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.815
	Confidence Interval	(2-Sided) 90%; 0.444 to 1.496
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left hand IPI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.2127
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.115
	Confidence Interval	(2-Sided) 90%; 0.965 to 1.289
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right hand IPI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.5661
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.059
	Confidence Interval	(2-Sided) 90%; 0.897 to 1.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Duration and Variability of ITI as Assessed by Dysdiadochomotography
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.
Time Frame	Baseline (Day -1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left hand ITI variability	0.036 (0.061)	0.015 (0.017)
Right hand ITI variability	0.053 (0.082)	0.017 (0.018)
Left hand ITI duration	0.064 (0.070)	0.006 (0.029)
Right hand ITI duration	0.094 (0.097)	0.022 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left hand ITI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0874
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.571
	Confidence Interval	(2-Sided) 90%; 1.018 to 2.424
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right hand ITI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.6431
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.18
	Confidence Interval	(2-Sided) 90%; 0.644 to 2.162
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left hand ITI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0389
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.193
	Confidence Interval	(2-Sided) 90%; 1.038 to 1.371
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right hand ITI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.1641
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.138
	Confidence Interval	(2-Sided) 90%; 0.976 to 1.327
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Variability of Peak TF as Assessed by Dysdiadochomotography
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.
Time Frame	Baseline (Day-1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left hand TF variability	3.50 (7.44)	9.98 (2.22)
Right hand TF variability	2.5 (10.87)	3.61 (2.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left hand TF variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.5668
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 90%; 0.755 to 1.147
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right hand TF variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.8686
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.978
	Confidence Interval	(2-Sided) 90%; 0.778 to 1.229
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Tapping Frequency as Assessed by Dysdiadochomotography
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.
Time Frame	Baseline (Day -1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	11	3
Left hand freq	-0.185 (0.402)	-0.073 (0.088)
Right hand freq	-0.236 (0.349)	-0.121 (0.189)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left hand freq statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.1244
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.879
	Confidence Interval	(2-Sided) 90%; 0.765 to 1.009
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right hand freq statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.3535
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.919
	Confidence Interval	(2-Sided) 90%; 0.789 to 1.069
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Duration and Variability of IOI as Assessed by Pedomotography
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.
Time Frame	Baseline (Day-1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	10	3
Left foot IOI variability	0.146 (0.353)	-0.1 (0.122)
Right foot IOI variability	0.120 (0.177)	0.090 (0.15)
Left foot IOI duration	0.109 (0.354)	-0.123 (0.199)
Right foot IOI duration	0.267 (0.461)	0.075 (0.164)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left foot IOI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.015
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	2.163
	Confidence Interval	(2-Sided) 90%; 1.295 to 3.614
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right foot IOI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.5136
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.274
	Confidence Interval	(2-Sided) 90%; 0.688 to 2.361
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left foot IOI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0218
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.560
	Confidence Interval	(2-Sided) 90%; 1.139 to 2.137
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right foot IOI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.3720
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.251
	Confidence Interval	(2-Sided) 90%; 0.825 to 1.899
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Duration and Variability of TD as Assessed by Pedomotography
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.
Time Frame	Baseline (Day-1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	10	3
Left foot TD variability	0.225 (0.332)	-0.056 (0.058)
Right foot TD variability	0.306 (0.566)	0.105 (0.140)
Left foot TD duration	0.179 (0.28)	-0.040 (0.106)
Right foot TD duration	0.358 (0.609)	0.083 (0.133)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left foot TD variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.915
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.911
	Confidence Interval	(2-Sided) 90%; 1.017 to 3.592
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right foot TD variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.2745
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.687
	Confidence Interval	(2-Sided) 90%; 0.762 to 3.737
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left foot TD duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.1148
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.598
	Confidence Interval	(2-Sided) 90%; 0.980 to 2.608
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right foot TD duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.3080
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.454
	Confidence Interval	(2-Sided) 90%; 0.789 to 2.679
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Duration and Variability of IPI as Assessed by Pedomotography
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.
Time Frame	Baseline (Day-1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	10	3
Left foot IPI variability	0.115 (0.248)	-0.108 (0.131)
Right foot IPI variability	0.117 (0.150)	0.098 (0.164)
Left foot IPI duration	0.117 (0.383)	-0.123 (0.206)
Right foot IPI duration	0.295 (0.469)	0.073 (0.158)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left foot IPI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0079
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	2.272
	Confidence Interval	(2-Sided) 90%; 1.381 to 3.737
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right foot IPI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0204
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.210
	Confidence Interval	(2-Sided) 90%; 0.686 to 2.133
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left foot IPI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0204
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.564
	Confidence Interval	(2-Sided) 90%; 1.144 to 2.138
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right foot IPI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.3144
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.269
	Confidence Interval	(2-Sided) 90%; 0.856 to 1.884
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Duration and Variability of ITI as Assessed by Pedomotography
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.
Time Frame	Baseline (Day-1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	10	3
Left foot ITI variability	0.003 (0.203)	-0.047 (0.108)
Right foot ITI variability	0.023 (0.118)	-0.016 (0.089)
Left foot ITI duration	-0.049 (0.232)	-0.076 (0.092)
Right foot ITI duration	-0.016 (0.121)	-0.012 (0.056)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left foot ITI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0324
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.914
	Confidence Interval	(2-Sided) 90%; 1.167 to 3.141
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right foot ITI variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.246
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.462
	Confidence Interval	(2-Sided) 90%; 0.85 to 2.515
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left foot ITI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.1057
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.387
	Confidence Interval	(2-Sided) 90%; 0.994 to 1.935
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right foot ITI duration statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.7342
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.074
	Confidence Interval	(2-Sided) 90%; 0.758 to 1.523
	Parameter Dispersion	Type: Value:
	Estimation Comments

25. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Variability of Peak TF as Assessed by Pedomotography
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.
Time Frame	Baseline (Day -1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	10	3
Left foot TF variability	11.63 (16.38)	-20.19 (34.30)
Right foot TF variability	-2.52 (22.35)	-18.31 (6.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left foot TF variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.1027
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.392
	Confidence Interval	(2-Sided) 90%; 0.997 to 1.943
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right foot TF variability statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.4494
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	1.158
	Confidence Interval	(2-Sided) 90%; 0.840 to 1.595
	Parameter Dispersion	Type: Value:
	Estimation Comments

26. Secondary Outcome

Title	Change From Baseline to Day 28 in the Mean Tapping Frequency as Assessed by Pedomotography
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.
Time Frame	Baseline (Day -1) to Day 28

Outcome Measure Data

Analysis Population Description

The PD population consisted of all subjects from the safety population who have not reported major protocol violations impacting Q-motor evaluation and who have a Q-motor evaluation assessed both at Baseline (Day -1) and at one post baseline visit.

Arm/Group Title	BN82451B	Placebo
Arm/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.	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.
Measure Participants	10	3
Left foot freq	-0.259 (0.513)	0.556 (0.678)
Right foot freq	-0.383 (0.481)	-0.18 (0.550)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Left foot freq statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.0350
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.699
	Confidence Interval	(2-Sided) 90%; 0.530 to 0.922
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BN82451B, Placebo
	Comments	Right foot freq statistical analysis is presented (BN82451B versus Placebo). 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.3556
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	GLS mean ratio
	Estimated Value	0.853
	Confidence Interval	(2-Sided) 90%; 0.640 to 1.136
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	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).
Adverse Event Reporting Description	AE data is reported as TEAEs.
Arm/Group Title	BN82451B		Placebo
Arm/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.		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.
All Cause Mortality
	BN82451B		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	BN82451B		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/3 (0%)
Other (Not Including Serious) Adverse Events
	BN82451B		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/14 (78.6%)		2/3 (66.7%)
Ear and labyrinth disorders
Ear swelling	1/14 (7.1%)	1	0/3 (0%)	0
Gastrointestinal disorders
Vomiting	3/14 (21.4%)	4	0/3 (0%)	0
Diarrhoea	2/14 (14.3%)	2	0/3 (0%)	0
Nausea	2/14 (14.3%)	3	0/3 (0%)	0
General disorders
Fatigue	3/14 (21.4%)	3	0/3 (0%)	0
Face oedema	2/14 (14.3%)	3	0/3 (0%)	0
Inflammation	1/14 (7.1%)	1	0/3 (0%)	0
Infections and infestations
Impetigo	1/14 (7.1%)	1	0/3 (0%)	0
Nasopharyngitis	0/14 (0%)	0	1/3 (33.3%)	1
Injury, poisoning and procedural complications
Laceration	1/14 (7.1%)	1	0/3 (0%)	0
Excoriation	1/14 (7.1%)	1	0/3 (0%)	0
Investigations
Gamma-glutamyltransferase increased	1/14 (7.1%)	1	0/3 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	2/14 (14.3%)	2	0/3 (0%)	0
Neck pain	0/14 (0%)	0	1/3 (33.3%)	1
Nervous system disorders
Headache	3/14 (21.4%)	4	0/3 (0%)	0
Dizziness	1/14 (7.1%)	1	0/3 (0%)	0
Hypoaesthesia	1/14 (7.1%)	1	0/3 (0%)	0
Depressed level of consciousness	1/14 (7.1%)	1	0/3 (0%)	0
Presyncope	2/14 (14.3%)	2	0/3 (0%)	0
Dyskinesia	1/14 (7.1%)	1	0/3 (0%)	0
Skin and subcutaneous tissue disorders
Rash	5/14 (35.7%)	5	0/3 (0%)	0
Acne	1/14 (7.1%)	1	0/3 (0%)	0
Rash generalised	1/14 (7.1%)	1	0/3 (0%)	0
Dry skin	1/14 (7.1%)	1	0/3 (0%)	0
Hyperhidrosis	1/14 (7.1%)	1	0/3 (0%)	0

Limitations/Caveats

The study was terminated prematurely due to subject recruitment problems before the completion of cohort 2.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI shall not proceed to publication or communication in connection with the subject matter of this Agreement or Results, without the prior written consent of Ipsen.