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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Preliminary Efficacy of NLX-112 versus Placebo in Levodopa-induced Dyskinesia in Parkinson’s Disease

    Summary
    EudraCT number
    		 2020-006053-22
    Trial protocol
    		 SE  
    Global end of trial date
    18 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Feb 2024
    First version publication date
    02 Feb 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NLX-112-DYS-101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05148884
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Neurolixis SAS
    Sponsor organisation address
    2 rue Georges Charpak, L’Arobase Le Causse Espace d’Entreprises, Labruguiere, France, FR-81290
    Public contact
    CEO, Neurolixis SAS, anewmantancredi@neurolixis.com
    Scientific contact
    CEO, Neurolixis SAS, anewmantancredi@neurolixis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Jan 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of NLX-112, titrated up to a maximum of 2 mg/day, compared to placebo during eight weeks of daily treatment in PD patients with LID.
    Protection of trial subjects
    The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and are compliant with the International Conference of Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) E6 (R2) guidance, the EU Clinical Trials Directive 2001/20/EC, and applicable local regulatory requirements. It was the responsibility of each Investigator or an authorized associate to give each potential study patient adequate verbal and written information before any study specific assessments were performed. The information included the objectives and the procedures of the study as well as any risks or inconvenience involved. It was emphasized that participation in the study was voluntary and that the patient could withdraw from participation at any time and for any reason, without any prejudice. All patients were given the opportunity to ask questions about the study and were given sufficient time to consider participation before signing the Informed consent form (ICF). Before performing any study-related procedures, the ICF was signed and personally dated by the patient and the Investigator. A copy of the patient information including the signed ICF was provided to the patient. Documentation of the discussion and the date of informed consent were recorded in the source documentation and in the electronic case report form (eCRF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Nov 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 27
    Worldwide total number of subjects
    27
    EEA total number of subjects
    27
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    12
    From 65 to 84 years
    14
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Potential participants in the study were identified according to the routines of the clinical study sites. Patients were recruited at 5 clinical sites, with a planned average of 4 to 6 patients per site.

    Pre-assignment
    Screening details
    		 A total of 35 patients were screened and 27 were randomized and dosed in the study. Eighteen patients were allocated to treatment with NLX-112 and 9 were allocated to placebo. Twenty-three patients, 15 on NLX-112 and 8 on placebo, completed the study.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    This was a double-blind study and the allocation of treatments was not disclosed until a clean file had been declared and the database had been locked. The IMP and the placebo were identical in appearance and taste.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NLX-112
    Arm description
    		 Patients were randomized to receive either active treatment with NLX-112 or placebo. This arm represents the patients that received NLX-112.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NLX-112
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients self-administered NLX-112 2 times each day, once in the morning and once in the evening, according to a dosing instruction sheet. Tablets were to be taken with approximately 240 mL water during a meal.

    Arm title
    		 Placebo
    Arm description
    		 Patients were randomized to receive either active treatment with NLX-112 or placebo. This arm represents the patients that received placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients self-administered placebo 2 times each day, once in the morning and once in the evening, according to a dosing instruction sheet. Tablets were to be taken with approximately 240 mL water during a meal.

    Number of subjects in period 1
    		NLX-112 Placebo
    Started
    18
    9
    Completed
    15
    8
    Not completed
    3
    1
         Consent withdrawn by subject
    3
    -
         Deep brain stimulation operation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NLX-112
    Reporting group description
    		 Patients were randomized to receive either active treatment with NLX-112 or placebo. This arm represents the patients that received NLX-112.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were randomized to receive either active treatment with NLX-112 or placebo. This arm represents the patients that received placebo.

    Reporting group values
    		 NLX-112 Placebo Total
    Number of subjects
    		 18 9 27
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 8 4 12
        From 65-84 years
    		 9 5 14
        85 years and over
    		 1 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.7 ( 9.7 ) 64.6 ( 6.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 4 12
        Male
    		 10 5 15

    End points

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    End points reporting groups
    Reporting group title
    NLX-112
    Reporting group description
    		 Patients were randomized to receive either active treatment with NLX-112 or placebo. This arm represents the patients that received NLX-112.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were randomized to receive either active treatment with NLX-112 or placebo. This arm represents the patients that received placebo.

    Primary: Frequency, intensity and seriousness of AEs

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    End point title
    		 Frequency, intensity and seriousness of AEs [1]
    End point description
    Number of patients with Adverse events (AEs) divided into categories of severity/intensity (grade 1 to grade 5 following the common terminology criteria for AEs (CTCAE) v5.0) and assessed relationship to IMP (unlikely, possibly or probably related).
    End point type
    Primary
    End point timeframe
    AEs (including SAEs) were collected from the start of IMP administration until the end-of-study visit.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, the end-point is reported using descriptive statistics only.
    End point values
    		 NLX-112 Placebo
    Number of subjects analysed
    18
    9
    Units: Number of subjects
        Any AE
    16
    7
        Any SAE
    0
    1
        Congenital Anomaly or Birth Defect
    0
    0
        Persistent/Significant Disability/Incapacity
    0
    0
        Requires or Prolongs Hospitalization
    0
    1
        Is Life Threatening
    0
    0
        Other Medically Important Serious Event
    0
    0
        Any AE leading to withdrawal from study
    1
    0
        Any AE leading to death
    0
    0
        Causality - Unlikely Related
    11
    4
        Causality - Possibly Related
    15
    5
        Causality - Probably Related
    3
    3
        Action taken with study drug - Dose Not Changed
    12
    6
        Action taken with study drug - Dose Reduced
    4
    3
        Action taken with study drug - Drug Interrupted
    0
    1
        Action taken with study drug - Not Applicable
    5
    2
        Severity - Mild
    14
    7
        Severity - Moderate
    10
    4
        Severity - Severe
    0
    1
        Severity - Life-Threatening
    0
    0
        Severity - Death
    0
    0
    No statistical analyses for this end point

    Primary: Clinically significant (CS) changes from baseline in electrocardiogram (ECG)

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    End point title
    		 Clinically significant (CS) changes from baseline in electrocardiogram (ECG) [2]
    End point description
    Number of patients with clinically significant changes from baseline in Electrocardiogram (Rate, PR interval, QRS duration, QT, QTcB, and QTcF). Any abnormalities were specified and documented as either clinically significant or not clinically significant. All ECGs were interpreted as normal or abnormal, not clinically significant by the Investigator at screening, baseline (Visit 2) and all subsequent post-dose visits to the clinics. There were no clinically relevant changes from baseline, and no obvious differences between the treatment groups, either in terms of overall ECG evaluations or change from baseline in individual ECG parameters.
    End point type
    Primary
    End point timeframe
    Visit 1 (Screening), Visit 2 (Baseline, Day 1), Visit 4 (Clinic Safety Visit, Day 14), Visit 5 (Clinic Safety Visit, Day 21), Visit 6 (Clinic Efficacy Visit, Day 28), Visit 7 (Clinic Efficacy Visit, Day 42) and Visit 9 (Follow-up Clinic Visit, Day 70).
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, the end-point is reported using descriptive statistics only.
    End point values
    		 NLX-112 Placebo
    Number of subjects analysed
    18 [3]
    9 [4]
    Units: Number of patients with CS changes
    0
    0
    Notes
    [3] - Full analysis set.
    [4] - Full analysis set.
    No statistical analyses for this end point

    Primary: Clinically significant (CS) changes from baseline in vital signs

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    End point title
    		 Clinically significant (CS) changes from baseline in vital signs [5]
    End point description
    Number of patients with clinically significant changes from baseline in vital signs (Systolic blood pressure (mmHg), diastolic blood pressure (mmHg), Heart rate, respiratory rate, body temperature). Any vital signs outside the normal ranges at each site were judged as either not clinically significant or clinically significant. There were no clinically relevant changes from baseline in mean vital signs parameters over time and no clinically relevant differences in any vital signs parameter between the active treatment group or the placebo group as assessed by the Investigator. Eighteen of the 27 randomized patients, 12 on NLX-112 and 6 on placebo, had abnormal vital signs assessed as not clinically significant on one or more occasions during the study. Of these, 2 patients, both on NLX-112, had abnormal vital signs assessed as significant.
    End point type
    Primary
    End point timeframe
    Visit 1 (Screening), Visit 2 (Baseline, Day 1), Visit 4 (Clinic Safety Visit, Day 14), Visit 5 (Clinic Safety Visit, Day 21), Visit 6 (Clinic Efficacy Visit, Day 28), Visit 7 (Clinic Efficacy Visit, Day 42) and Visit 9 (Follow-up Clinic Visit, Day 70).
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, the end-point is reported using descriptive statistics only.
    End point values
    		 NLX-112 Placebo
    Number of subjects analysed
    18 [6]
    9 [7]
    Units: Number of patients with CS changes
    2
    0
    Notes
    [6] - Full analysis set.
    [7] - Full analysis set.
    No statistical analyses for this end point

    Primary: Clinically significant (CS) changes from baseline in safety laboratory parameters

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    End point title
    		 Clinically significant (CS) changes from baseline in safety laboratory parameters [8]
    End point description
    Number of patients with clinically significant changes from baseline in safety laboratory parameters. Any lab values outside the normal ranges were judged as not clinically significant or clinically significant. There were no clinically relevant changes from baseline in mean clinical chemistry, hematology, coagulation or urinalysis parameters over time and no clinically relevant differences in any laboratory parameter between the active treatment group or the placebo group as assessed by the Investigator. All 27 randomized patients had abnormal laboratory values on one or more occasions over the course of the study. A majority of the abnormal laboratory values were assessed as not clinically significant. No coagulation parameter was assessed as abnormal. Three patients had abnormal laboratory values assessed as clinically significant, which in 2 cases were reported as AEs (inflammatory marker increased and hyperglycemia, both assessed as unrelated to treatment with NLX-112).
    End point type
    Primary
    End point timeframe
    Visit 1 (Screening), Visit 2 (Baseline, Day 1), Visit 4 (Clinic Safety Visit, Day 14), Visit 5 (Clinic Safety Visit, Day 21), Visit 6 (Clinic Efficacy Visit, Day 28), Visit 7 (Clinic Efficacy Visit, Day 42) and Visit 9 (Follow-up Clinic Visit, Day 70).
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, the end-point is reported using descriptive statistics only.
    End point values
    		 NLX-112 Placebo
    Number of subjects analysed
    18 [9]
    9 [10]
    Units: Number of patients with CS changes
    2
    1
    Notes
    [9] - Full analysis set.
    [10] - Full analysis set.
    No statistical analyses for this end point

    Primary: Clinically significant changes (CS) from baseline in physical examinations

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    End point title
    		 Clinically significant changes (CS) from baseline in physical examinations [11]
    End point description
    Number of clinically significant changes in physical examination investigated by general appearance, head, ears, eyes, nose, throat, neck, skin, cardiovascular system, respiratory system, abdominal system, and nervous system. Any abnormalities were specified and documented as either clinically significant or not clinically significant. There were no clinically relevant changes from baseline (screening) to Visit 9 (Day 70±7 days) in physical examination findings between the active treatment group or the placebo group as assessed by the Investigator. Fourteen of the 27 randomized patients had a physical examination assessed as abnormal, clinically significant for one or more organ system at either the screening visit (Visit 1) or Visit 9 or both. Clinically significant findings were most commonly associated with the nervous system and the underlying PD (12 patients, 8 on NLX-112 and 4 on placebo) and were observed both at screening and at Visit 9 (10 patients).
    End point type
    Primary
    End point timeframe
    Visit 1 (Screening) and Visit 9 (Follow-up Clinic Visit, Day 70).
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, the end-point is reported using descriptive statistics only.
    End point values
    		 NLX-112 Placebo
    Number of subjects analysed
    18 [12]
    9 [13]
    Units: Number of patients with CS changes
    8
    4
    Notes
    [12] - Full analysis set.
    [13] - Full analysis set.
    No statistical analyses for this end point

    Primary: Suicidal ideation/behavior as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS)

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    End point title
    		 Suicidal ideation/behavior as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) [14]
    End point description
    Number of patients with changes from baseline in suicidal ideation/behavior as assessed by C-SSRS questionnaire with no total score summation. The scale contains 6 “yes” or “no” questions in which respondents were asked to indicate whether they have experienced several thoughts or feelings relating to suicide over the past month and behavior over their lifetime and past 3 months. Each question addresses a different component of the respondent's suicide ideation severity and behavior. Q1: wish to be dead, Q2: non-specific suicidal thoughts, Q3-5: more specific suicidal thoughts and intent to act, Q6: suicidal behavior over the respondent’s lifetime and past 3 months, If the respondent answered “yes” to Q2, he/she was instructed to answer Q 3-5. If the respondent answered “no” to Q2, he/she could skip to Q6. No patient indicated a change in suicidal ideation/behavior from baseline until Visit 9 (Day 70±7 days).
    End point type
    Primary
    End point timeframe
    The baseline scale was used at screening (Visit 1) and the follow-up scale at all subsequent visits (Visit 2, 4-7, 9)
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, the end-point is reported using descriptive statistics only.
    End point values
    		 NLX-112 Placebo
    Number of subjects analysed
    18 [15]
    9 [16]
    Units: Number of patients with changes
    0
    0
    Notes
    [15] - Full analysis set.
    [16] - Full analysis set.
    No statistical analyses for this end point

    Secondary: Change from baseline at the final efficacy clinic visit (Day 42), after a 150% L-DOPA dose challenge, in the Unified Dyskinesia Rating Scale (UDysRS) total score - Absolute change from baseline

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    End point title
    		 Change from baseline at the final efficacy clinic visit (Day 42), after a 150% L-DOPA dose challenge, in the Unified Dyskinesia Rating Scale (UDysRS) total score - Absolute change from baseline
    End point description
    The UDysRS is a rating instrument designed to assess the core features of dyskinesia in PD. The UDysRS consists of 4 parts: • Part 1, historical disability with regard to the patient’s perceptions of the impact on activities of ADL of on-dyskinesia. • Part 2, historical disability with regard to the patient’s perceptions of the impact on ADL of off-dystonia. • Part 3, objective impairment, which assesses severity of dyskinesia, affected body parts, and type of impairment (choreic vs. dystonic). • Part 4, objective disability, based on an evaluation of Part 3 activities. Each item in the UDysRS was scored from 0 to 4, with a possible maximum total score of 104. The UDysRS Parts 3 and 4 were repeated 3 times after each L-DOPA challenge, 30 minutes apart, and were hence performed approximately 30, 60 and 90 minutes after each challenge.
    End point type
    Secondary
    End point timeframe
    At baseline (Day 1, Visit 2), and Day 42 (Visits 7), starting approximately 30 minutes after the L-DOPA challenge.
    End point values
    		 NLX-112 Placebo
    Number of subjects analysed
    15 [17]
    7 [18]
    Units: UDysRS total score
    arithmetic mean (standard deviation)
        Visit 2 Baseline
    31.6 ( 9.7 )
    39.9 ( 14.2 )
        Visit 7 Clinic Efficacy Visit
    -6.3 ( 7.0 )
    -2.4 ( 9.7 )
    Notes
    [17] - Per protocol analysis set.
    [18] - Per protocol analysis set.
    No statistical analyses for this end point

    Secondary: Change from baseline in UDysRS total score at Day 28, after a 150% L-DOPA dose challenge - Absolute change from baseline

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    End point title
    		 Change from baseline in UDysRS total score at Day 28, after a 150% L-DOPA dose challenge - Absolute change from baseline
    End point description
    The UDysRS is a rating instrument designed to assess the core features of dyskinesia in PD. The UDysRS consists of 4 parts: • Part 1, historical disability with regard to the patient’s perceptions of the impact on activities of ADL of on-dyskinesia. • Part 2, historical disability with regard to the patient’s perceptions of the impact on ADL of off-dystonia. • Part 3, objective impairment, which assesses severity of dyskinesia, affected body parts, and type of impairment (choreic vs. dystonic). • Part 4, objective disability, based on an evaluation of Part 3 activities. Each item in the UDysRS was scored from 0 to 4, with a possible maximum total score of 104. The UDysRS Parts 3 and 4 were repeated 3 times after each L-DOPA challenge, 30 minutes apart, and were hence performed approximately 30, 60 and 90 minutes after each challenge.
    End point type
    Secondary
    End point timeframe
    At baseline (Day 1, Visit 2) and Day 28 (Visits 6), starting approximately 30 minutes after the L-DOPA challenge.
    End point values
    		 NLX-112 Placebo
    Number of subjects analysed
    15 [19]
    7 [20]
    Units: UDysRS total score
    arithmetic mean (standard deviation)
        Visit 2 Baseline
    31.6 ( 9.7 )
    39.9 ( 14.2 )
        Visit 6 Clinic Efficacy Visit
    -4.1 ( 9.3 )
    -2.0 ( 4.9 )
    Notes
    [19] - Per protocol analysis set.
    [20] - Per protocol analysis set.
    No statistical analyses for this end point

    Secondary: Change from baseline in total objective score (Parts 3, 4) of the UDysRS at Day 28 and Day 42, after a 150% L-DOPA dose challenge - Absolute change from baseline

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    End point title
    		 Change from baseline in total objective score (Parts 3, 4) of the UDysRS at Day 28 and Day 42, after a 150% L-DOPA dose challenge - Absolute change from baseline
    End point description
    The UDysRS is a rating instrument designed to assess the core features of dyskinesia in PD. The UDysRS consists of 4 parts: • Part 1, historical disability with regard to the patient’s perceptions of the impact on activities of ADL of on-dyskinesia. • Part 2, historical disability with regard to the patient’s perceptions of the impact on ADL of off-dystonia. • Part 3, objective impairment, which assesses severity of dyskinesia, affected body parts, and type of impairment (choreic vs. dystonic). • Part 4, objective disability, based on an evaluation of Part 3 activities. Each item in the UDysRS was scored from 0 to 4, with a possible maximum total score of 104.
    End point type
    Secondary
    End point timeframe
    At baseline (Day 1, Visit 2), Day 28 and Day 42 (Visits 6 and 7), starting approximately 30 minutes after the L-DOPA challenge.
    End point values
    		 NLX-112 Placebo
    Number of subjects analysed
    15 [21]
    7 [22]
    Units: UDysRS total score
    arithmetic mean (standard deviation)
        Visit 2 Baseline
    15.5 ( 6.2 )
    18.1 ( 7.9 )
        Visit 6 Clinic Efficacy Visit
    -1.7 ( 4.3 )
    -1.0 ( 1.8 )
        Visit 7 Clinic Efficacy Visit
    -3.1 ( 4.2 )
    -0.1 ( 3.8 )
    Notes
    [21] - Per protocol analysis set.
    [22] - Per protocol analysis set.
    No statistical analyses for this end point

    Secondary: Change from baseline in ON Time Without Troublesome Dyskinesia (ON Without Dyskinesia plus ON With Non-troublesome Dyskinesia) based on a PD Home Dyskinesia Diary - Absolute change from baseline

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    End point title
    		 Change from baseline in ON Time Without Troublesome Dyskinesia (ON Without Dyskinesia plus ON With Non-troublesome Dyskinesia) based on a PD Home Dyskinesia Diary - Absolute change from baseline
    End point description
    A PD Home Dyskinesia Diary (electronic) as completed by the patient and/or caregiver with concordance in ON time with dyskinesia between study staff and patient. The diary was integrated in the Kinesia 360 wearable dyskinesia assessment system and was based on the PD Home Diary developed by Hauser et al 2004. The diary was used to score 5 different conditions in 30-minute time intervals during 2x24 hours prior to Visit 2, Visit 6 and Visit 7: • ASLEEP; • OFF; • ON (i.e., adequate control of PD symptoms) without dyskinesia; • ON with non-troublesome dyskinesia; • ON with troublesome dyskinesia.
    End point type
    Secondary
    End point timeframe
    The patient and/or caregiver completed a PD Home Dyskinesia eDiary diary in 30-minute time intervals during 2x24 hours prior to baseline (Visit 2), and during 4x24 hours prior to Day 28 (Visit 6) and Day 42 (Visit 7).
    End point values
    		 NLX-112 Placebo
    Number of subjects analysed
    15 [23]
    7 [24]
    Units: ON and OFF ratio
    arithmetic mean (standard deviation)
        Baseline
    0.576 ( 0.199 )
    0.548 ( 0.192 )
        Titration
    0.0569 ( 0.158 )
    0.0245 ( 0.135 )
        Steady-State
    0.0523 ( 0.193 )
    0.0335 ( 0.154 )
    Notes
    [23] - Per protocol analysis set. Titration n = 13, Steady-State n = 12
    [24] - Per protocol analysis set. Titration n = 6, Steady-State n = 6
    No statistical analyses for this end point

    Secondary: Change from baseline in Unified Parkinson’s Disease Rating Scale (UPDRS) scores (Part III, motor examination) - Absolute change from baseline

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    End point title
    		 Change from baseline in Unified Parkinson’s Disease Rating Scale (UPDRS) scores (Part III, motor examination) - Absolute change from baseline
    End point description
    The UPDRS is one of the most widely-used rating scales employed in the assessment of PD. The UPDRS consists of 4 parts: • Part I assesses non-motor experiences of daily living, such as cognitive impairment and depressed mood. • Part II assesses motor experiences of daily living, such as speech and eating tasks. • Part III is a motor examination conducted by the clinician, including assessments of symptoms such as rigidity and tremor. • Part IV is an assessment of motor complications, such as time spent with dyskinesia and functional impact of dyskinesias. Each item in the UPDRS was scored from 0 to 4, and the individual scores were summed to give a total score that indicates the severity of the disease, with a score of 0 indicating no disability and a score of 199 being the most severe (indicating total disability).
    End point type
    Secondary
    End point timeframe
    At baseline (Day 1, Visit 2), Day 28 (Visit 6), Day 42 (Visit 7) and Day 70 (Visit 9).
    End point values
    		 NLX-112 Placebo
    Number of subjects analysed
    15 [25]
    7 [26]
    Units: UPDRS total score
    arithmetic mean (standard deviation)
        Visit 2 Baseline
    17.5 ( 9.4 )
    17.0 ( 10.3 )
        Visit 6 Clinic Efficacy Visit
    -3.7 ( 4.7 )
    1.3 ( 6.9 )
        Visit 7 Clinic Efficacy Visit
    -3.7 ( 4.6 )
    0.1 ( 8.2 )
        Visit 9 Follow-up Clinic Visit
    -2.7 ( 5.5 )
    -2.4 ( 2.9 )
    Notes
    [25] - Per protocol analysis set.
    [26] - Per protocol analysis set.
    No statistical analyses for this end point

    Secondary: Change from baseline in UPDRS combined scores (Parts I, II, III and IV) - Absolute change from baseline

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    End point title
    		 Change from baseline in UPDRS combined scores (Parts I, II, III and IV) - Absolute change from baseline
    End point description
    The UPDRS is one of the most widely-used rating scales employed in the assessment of PD. The UPDRS consists of 4 parts: • Part I assesses non-motor experiences of daily living, such as cognitive impairment and depressed mood. • Part II assesses motor experiences of daily living, such as speech and eating tasks. • Part III is a motor examination conducted by the clinician, including assessments of symptoms such as rigidity and tremor. • Part IV is an assessment of motor complications, such as time spent with dyskinesia and functional impact of dyskinesias. Each item in the UPDRS was scored from 0 to 4, and the individual scores were summed to give a total score that indicates the severity of the disease, with a score of 0 indicating no disability and a score of 199 being the most severe (indicating total disability).
    End point type
    Secondary
    End point timeframe
    At baseline (Day 1, Visit 2), Day 28 (Visit 6), Day 42 (Visit 7) and Day 70 (Visit 9).
    End point values
    		 NLX-112 Placebo
    Number of subjects analysed
    15 [27]
    7 [28]
    Units: UPDRS total score
    arithmetic mean (standard deviation)
        Visit 2 Baseline
    37.0 ( 13.3 )
    41.3 ( 15.0 )
        Visit 6 Clinic Efficacy Visit
    -6.5 ( 7.6 )
    -3.6 ( 7.0 )
        Visit 7 Clinic Efficacy Visit
    -5.7 ( 6.0 )
    -3.9 ( 9.3 )
        Visit 9 Follow-up Clinic Visit
    -4.4 ( 9.0 )
    -7.3 ( 5.4 )
    Notes
    [27] - Per protocol analysis set.
    [28] - Per protocol analysis set.
    No statistical analyses for this end point

    Secondary: Clinical Global Impression of Change (CGI-C) in overall PD symptoms

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    End point title
    		 Clinical Global Impression of Change (CGI-C) in overall PD symptoms
    End point description
    The CGI-C is a clinician-oriented scale that assesses the total improvement in the patient's condition relative to the clinical global impression of severity (CGI-S) scale conducted at baseline. The CGI-C rates the patient’s condition from 0 to 7, with a rating of 0 indicating “no assessment”, a rating of 1 indicating “very much better”, and a rating of 7 indicating “very much worse”.
    End point type
    Secondary
    End point timeframe
    Patients rated their global condition using CGI-S at baseline (Day 1, Visit 2) and CGI-C at Day 28 (Visit 6) and Day 42 (Visit 7).
    End point values
    		 NLX-112 Placebo
    Number of subjects analysed
    15 [29]
    7 [30]
    Units: Number of subjects
        Visit 2 Baseline - Normal, not at all ill
    3
    2
        Visit 2 Baseline - Moderately ill
    8
    2
        Visit 2 Baseline - Markedly ill
    3
    2
        Visit 2 Baseline - Severely ill
    1
    1
        Visit 6 Clinic Efficacy Visit - Much improved
    2
    2
        Visit 6 Clinic Efficacy Visit - Minimally improved
    3
    0
        Visit 6 Clinic Efficacy Visit - No change
    9
    4
        Visit 6 Clinic Efficacy Visit - Minimally worse
    1
    1
        Visit 7 Clinic Efficacy Visit - Very much improved
    1
    0
        Visit 7 Clinic Efficacy Visit - Much improved
    4
    1
        Visit 7 Clinic Efficacy Visit - Minimally improved
    3
    1
        Visit 7 Clinic Efficacy Visit - No change
    6
    5
        Visit 7 Clinic Efficacy Visit - Minimally worse
    1
    0
    Notes
    [29] - Per protocol analysis set.
    [30] - Per protocol analysis set.
    No statistical analyses for this end point

    Secondary: Change from baseline in dyskinesia scores measured by the Kinesia 360 (Great Lakes Neurotechnologies, Inc) wearable dyskinesia assessment system - Absolute change from baseline

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    End point title
    		 Change from baseline in dyskinesia scores measured by the Kinesia 360 (Great Lakes Neurotechnologies, Inc) wearable dyskinesia assessment system - Absolute change from baseline
    End point description
    The Kinesia 360 (Great Lakes Neurotechnologies, Inc) wearable dyskinesia assessment system was used to monitor dyskinesias. The Kinesia 360 motor assessment system is intended to provide a low burden method for remote, continuous measurement of patient symptoms. Sensors worn on the wrist and ankle combined with a mobile application continuously record data for assessment of tremor, slowness, dyskinesia and mobility. Data from the motion sensors was uploaded to the Kinesia Web Portal and algorithms were used to detect symptoms and calculate severity scores every 2 minutes on a scale shown to be highly correlated with clinician ratings. Sensors recorded data all day and were recharged overnight for extended home use.
    End point type
    Secondary
    End point timeframe
    Wearable data collection of dyskinesias took place during a 2-day period prior to the baseline visit (Day 1, Visit 2) and a 4-day period prior to Day 28 (Visit 6) and Day 42 (Visit 7).
    End point values
    		 NLX-112 Placebo
    Number of subjects analysed
    15 [31]
    7 [32]
    Units: Dyskinesia detect scores
    arithmetic mean (standard deviation)
        Baseline
    0.1807 ( 0.1955 )
    0.2855 ( 0.3322 )
        Titration
    -0.06517 ( 0.06722 )
    -0.009172 ( 0.1353 )
        Steady-State
    -0.009327 ( 0.1243 )
    -0.01630 ( 0.3166 )
    Notes
    [31] - Per protocol analysis set. Baseline n = 12, Titration n = 8, Steady-State n = 6
    [32] - Per protocol analysis set. Baseline n = 5, Titration n = 3, Steady-State n = 3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs (including SAEs) were collected from the start of IMP administration until the end-of-study visit.
    Adverse event reporting additional description
    The grading of the severity/intensity (grade 1 to grade 5) of AEs followed the common terminology criteria for AEs (CTCAE) v5.0 [24]. AEs were assessed as unlikely, possibly or probably related to the IMP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    NLX-112
    Reporting group description
    		 Patients were randomized to receive either active treatment with NLX-112 or placebo. This arm represents the patients that received NLX-112.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were randomized to receive either active treatment with NLX-112 or placebo. This arm represents the patients that received placebo.

    Serious adverse events
    		 NLX-112 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 NLX-112 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 18 (88.89%)
    7 / 9 (77.78%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Orthostatic hypotension
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 9 (11.11%)
         occurrences all number
    2
    1
    Systolic hypertension
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 9 (22.22%)
         occurrences all number
    2
    3
    Psychiatric disorders
    Apathy
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Dissociation
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Hallucination
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Illusion
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Irritability
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Rapid eye movement sleep behavior disorder
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Stress
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Inflammatory marker increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    Incorrect dose administered
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Lip injury
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Product communication issue
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 9 (11.11%)
         occurrences all number
    2
    1
    Dyskinesia
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Headache
         subjects affected / exposed
    3 / 18 (16.67%)
    2 / 9 (22.22%)
         occurrences all number
    4
    3
    On and off phenomenon
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Parkinsonism
         subjects affected / exposed
    3 / 18 (16.67%)
    3 / 9 (33.33%)
         occurrences all number
    3
    7
    Parosmia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Restless legs syndrome
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Somnolence
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Taste disorder
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Vertigo
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 9 (11.11%)
         occurrences all number
    2
    1
    Eye disorders
    Binocular eye movement disorder
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Dry eye
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Erythema of eyelid
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Eye pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Swelling of eyelid
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Dry mouth
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Gastritis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    4 / 18 (22.22%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    Oral pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 9 (11.11%)
         occurrences all number
    2
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Micturition urgency
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Pollakiuria
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Muscle spasms
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 9 (22.22%)
         occurrences all number
    1
    2
    Respiratory tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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