Study to Assess the Safety, Tolerability and Preliminary Efficacy of NLX-112 Versus Placebo in L-dopa-induced Dyskinesia

Neurolixis SAS27 enrolled

Overview

This is a double-blind, randomized, placebo-controlled Phase 2a study evaluating the safety, tolerability, and preliminary efficacy of up to 2 mg/day (1 mg BID) of NLX-112 versus placebo in patients with moderate to severe L-DOPA induced dyskinesia (LID) in Parkinson's disease (PD). NLX-112 will be up-titrated to either 2 mg/day or to the highest well-tolerated dose less than 2 mg/day over 4 weeks, maintained at the well-tolerated dose for an additional 2 weeks, and then down-titrated over 2 weeks.

This is a two-arm, double-blind, randomized, placebo-controlled Phase 2a study evaluating the safety, tolerability, and preliminary efficacy of up to 2 mg/day of NLX 112 versus placebo in patients with moderate to severe L-DOPA induced dyskinesia (LID) in Parkinson's disease (PD). NLX-112 will be up-titrated to either 2 mg/day (1 mg BID) or to the highest well-tolerated dose less than 2 mg/day over 4 weeks, maintained at the well-tolerated dose for an additional 2 weeks, and then down-titrated over 2 weeks. Patients will report to the study clinic for a screening visit (Visit 1), followed by a baseline visit on Day 1 (Visit 2) where patients will be randomized and begin treatment. Two remote safety visits over telephone (Days 7 and 49 \[Visit 3 and Visit 8\]) will be conducted. Once treatment has commenced, there will be 2 in-person safety visits to the clinic (Days 14 and 21 \[Visit 4 and Visit 5\]), 2 in-person efficacy visits to the clinic (Days 28 and 42 \[Visit 6 and Visit 7\]) and one follow-up in person final safety visit (Day 70 \[Visit 9\]). In total, patients will report to the clinic for 7 in-person visits. Patients entering the study will be randomized in a 2:1 ratio (16:8 patients) to receive either NLX 112 or placebo. At Visits 2, 6 and 7, efficacy assessments will start 30 minutes after the patient has taken 150% of his or her regular L-DOPA dose, when the patient is ON and experiencing typical dyskinesia. A PD Home Dyskinesia Diary (electronic) will be completed by the patients and/or caregiver with concordance in ON time with dyskinesia between study staff and patient. Two consecutive 24-hour diaries will be completed prior to randomization (baseline, Visit 2) and prior to the clinic visits on Days 28 and 42 (Visits 6 and 7). A wearable dyskinesia assessment device will be used to monitor dyskinesias during a 2-day period prior to the baseline visit (Day 1, Visit 2) and a 2-day period prior to the clinic visits on Days 28 and 42 (Visits 6 and 7, respectively). Blood will be collected for possible NLX-112 plasma concentration measurements on Days 14, 21, 28, 42 and 70 (Visits 4, 5, 6, 7 and 9).

Study Type

INTERVENTIONAL

Conditions

Medication-Induced Dyskinesia

Interventions

NLX-112DRUG

NLX-112 will be supplied as tablets containing 0.25 mg NLX-112. NLX-112 is a structurally novel centrally acting, high-efficacy selective 5-HT1A receptor agonist with nanomolar affinity for 5-HT1A receptors. Proposed as a treatment for L-DOPA-induced-dyskinesia in Parkinson's disease.

PlaceboDRUG

Placebo will be matching tablets (identical weight, shape and color) without NLX-112.

Eligibility

Sex: ALLMin age: 30 YearsMax age: 85 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Patient is 30 - 85 years old (inclusive) with a diagnosis of idiopathic PD according to the UK Parkinson's Disease Society Brain Bank Clinical Diagnosis criteria. 2. PD patient is stably and optimally treated with L-DOPA; other anti-PD treatments are allowed if used for at least 4 weeks of previous continuous treatment. 3. Patient agrees to be challenged with 150% of their normal L-DOPA dose (maximum L-DOPA dose 250 mg) 30 minutes prior to efficacy assessments at baseline (Visit 2) and at the 2 efficacy clinic visits (Visits 6 and 7). 4. PD patient exhibits troublesome peak-dose LID, confirmed by a score of at least 1 on part IV, item 33 (disability) of the UPDRS at screening (Visit 1) and at Day 1 (baseline, Visit 2). 5. At least 90 minutes in total for each 24-hour period during 2 days are indicated as "ON with troublesome dyskinesia" (according to the PD Home Dyskinesia Diary) prior to Day 1 (baseline, Visit 2). 6. Patient (and/or caregiver) demonstrates ability to accurately complete the PD Home Dyskinesia Diary entries during the screening visit. 7. Patient can read well enough to understand the informed consent document and other subject materials. 8. Female patients of child-bearing potential must have a negative urine pregnancy test at screening (Visit 1) and on Day 1 (Visit 2), must agree to avoid pregnancy during the study, and must practice abstinence (only allowed when this is the preferred and usual lifestyle of the subject) or must agree to use a highly effective method of contraception with a failure rate of \< 1% to prevent pregnancy (combined \[oestrogen and progestogen containing\] hormonal contraception associated with inhibition of ovulation \[oral, intravaginal, transdermal\], progestogen-only hormonal contraception associated with inhibition of ovulation \[oral, injectable, implantable\], intrauterine device \[IUD\] or intrauterine hormone-releasing system \[IUS\]) starting from 4 weeks prior to administration of the study drug and continuing during the course of the study until 4 weeks after last after IMP administration. Female subjects must agree to refrain from donating eggs from the date of dosing until 3 months after dosing with the IMP. Their male partner must agree to use a condom during the same time frame if he has not undergone vasectomy. Females of non-childbearing potential are defined as pre-menopausal females who are sterilised (tubal ligation or permanent bilateral occlusion of fallopian tubes); or females who have undergone hysterectomy or bilateral oophorectomy; or post-menopausal defined as 12 months of amenorrhea (in questionable cases a blood sample with detection of follicle stimulating hormone \[FSH\] 25-140 IE/L is confirmatory). Male patients must be either vasectomised, consent to use condom or practice sexual abstinence to prevent pregnancy and drug exposure of a partner and refrain from donating sperm from the date of dosing until 3 months after dosing with the IMP. Their female partner of child-bearing potential must use highly effective contraceptive methods with a failure rate of \< 1% to prevent pregnancy (see above) during the same period. Exclusion Criteria: 1. Patient has severe PD with a Hoehn and Yahr stage = 5. 2. Patient has unstable medical status, prior brain surgery against tumors or hemorrhage (excluding deep brain stimulation \[DBS\], i.e., DBS patients will be allowed to be enrolled) or is scheduled to receive surgery during the trial period. 3. Patient has orthostatic hypotension: a decrease in systolic blood pressure (at least 20 mm Hg) or diastolic blood pressure (at least 10 mm Hg) within 3 minutes of the patient standing up, compared to pressures obtained while in a sitting position for at least 5 minutes. At screening and baseline visits (Visit 1 and Visit 2), vital signs to assess orthostatic hypotension will be conducted in triplicate, 15-20 minutes apart, with the average of the 3 assessments used for exclusion. 4. Patient has dementia (MMSE \<20). 5. Patient has clinically significant renal or liver disorder. 6. Patient currently exhibits generalized obsessive-compulsive disorder, panic disorder, bipolar disorder, post-traumatic stress syndrome (PTSD), clinically significant parasomnias or any other psychotic disorder as established by structured clinical interview for DSM disorders (SCID). Visual hallucinations are allowed. 7. Any suicidal actions in the past 2 years (per investigator judgement i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behavior). 8. Any suicidal ideation of type 4 or 5 in the C-SSRS in the past 3 months (i.e. active suicidal thought with intent but without specific plan, or active suicidal thought with plan and intent). 9. Patient has taken an anti-convulsant, an anti-psychotic (except quetiapine), pindolol, tertatolol or buspirone within 4 weeks of baseline (Day 1, Visit 2). 10. Patient has taken any medication, within 4 weeks of baseline (Day 1, Visit 2) that inhibits or up-regulates CYP4503A4. 11. Patient is concurrently participating in another investigational drug trial or has participated in another investigational drug trial within the past 3 months. 12. Patient is at high risk of non-compliance in the Investigator's opinion.

Locations (5)

Sahlgrenska Hospital

Gothenburg, Sweden

Skåne University Hospital

Lund, Sweden

ASC Torsplan

Stockholm, Sweden

Karolinska University Hospital, Solna

Stockholm, Sweden

CTC Clinical Trial Consultants AB (CTC)

Outcomes

Primary Outcomes

Number of Participants With Adverse Events (AEs)

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). AEs (including SAEs) were collected from the start of IMP administration until the end-of-study visit.

Time frame: AEs (including SAEs) were collected from the start of IMP administration until the end-of-study visit. Through study completion, an average of 10 weeks.

Number of Participants With Any Clinically Significant Changes From Baseline in Electrocardiogram (ECG)

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.

Time frame: 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).

Number of Patients With Any Clinically Significant Changes From Baseline in Vital Signs

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 by the clinician.

Number of Patients With Any Clinically Significant Changes From Baseline in Safety Laboratory Parameters

Number of patients with clinically significant changes from baseline in safety laboratory parameters. Any lab values outside the normal ranges at each site were judged as not clinically significant or clinically significant.

Data from ClinicalTrials.gov

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Secondary Outcomes

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 - Change From Baseline

The Unified Dyskinesia Rating Scale (UDysRS) is a rating instrument designed to assess the core features of dyskinesia in Parkinson´s Disease. The UDysRS consists of 4 parts: * Part 1, historical disability with regard to the patient's perceptions of the impact on activities of daily living (ADL) of on-dyskinesia (11 items). * Part 2, historical disability with regard to the patient's perceptions of the impact on ADL of off-dystonia (4 items). * Part 3, objective impairment, which assesses severity of dyskinesia, affected body parts, and type of impairment (choreic vs. dystonic) (7items). * Part 4, objective disability, based on an evaluation of Part 3 activities (4 items). Each item in the UDysRS was scored from 0 to 4, with a possible maximum total score sum of 104 where a higher score indicates a worse outcome. The UDysRS Parts 3 and 4 were repeated 3 times after each L-dopa challenge, and the timepoint with the worst outcome was used to calculate total score sum

Time frame: At baseline (Day 1, Visit 2), and Day 42 (Visits 7)

Change From Baseline in UDysRS Total Score at Day 28, After a 150% L-DOPA Dose Challenge - Change From Baseline

Time frame: At baseline (Day 1, Visit 2) and Day 28 (Visits 6)

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 - Change From Baseline

The Unified Dyskinesia Rating Scale (UDysRS) is a rating instrument designed to assess the core features of dyskinesia in Parkinson´s Disease. The UDysRS consists of 4 parts: * Part 1, historical disability with regard to the patient's perceptions of the impact on activities of daily living (ADL) of on-dyskinesia (11 items). * Part 2, historical disability with regard to the patient's perceptions of the impact on ADL of off-dystonia (4 items). * Part 3, objective impairment, which assesses severity of dyskinesia, affected body parts, and type of impairment (choreic vs. dystonic) (7items). * Part 4, objective disability, based on an evaluation of Part 3 activities (4 items). Each item in the UDysRS was scored from 0 to 4, with a possible total score sum for parts 3 and 4 of 44, where a higher score indicates a worse outcome. The UDysRS Parts 3 and 4 were repeated 3 times after each levodopa challenge, and the timepoint with the worst outcome was used to calculate total score sum.

Time frame: At baseline (Day 1, Visit 2), Day 28 and Day 42 (Visits 6 and 7)

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 - Change From Baseline

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 (Baseline), Visit 6 (Titration) and Visit 7 (Steady state): * ASLEEP; * OFF; * ON (i.e., adequate control of PD symptoms) without dyskinesia; * ON with non-troublesome dyskinesia; * ON with troublesome dyskinesia. Presented as the ratio of ON Time without troublesome dyskinesia (the sum of the time in ON without dyskinesia together with the time in ON with non-troublesome dyskinesia) compared with the total awake time (ON and OFF).

Time frame: Baseline - prior to Day 1 (Visit 2), Titration - prior to Day 28 (Visit 6), and Steady state prior to Day 42 (Visit 7).

Change From Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) Scores (Part III, Motor Examination) - Change From Baseline

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 (4 items). * Part II assesses motor experiences of daily living, such as speech and eating tasks (13 items). * Part III is a motor examination conducted by the clinician, including assessments of symptoms such as rigidity and tremor (27 items). * Part IV is an assessment of motor complications, such as time spent with dyskinesia and functional impact of dyskinesias (11 items). Each item in the UPDRS was scored from 0 to 4 (7 items in Part IV was scored 0 to 1), 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). Total score sum for Part III alone is 108.

Time frame: At baseline (Day 1, Visit 2), Day 28 (Visit 6), Day 42 (Visit 7) and Day 70 (Visit 9).

Change From Baseline in UPDRS Combined Scores (Parts I, II, III and IV) - Change From Baseline

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 (4 items). Part II assesses motor experiences of daily living, such as speech and eating tasks (13 items). Part III is a motor examination conducted by the clinician, including assessments of symptoms such as rigidity and tremor (27 items). Part IV is an assessment of motor complications, such as time spent with dyskinesia and functional impact of dyskinesias (11 items). Each item in the UPDRS was scored from 0 to 4 (7 items in Part IV was scored 0 to 1), 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).

Time frame: At baseline (Day 1, Visit 2), Day 28 (Visit 6), Day 42 (Visit 7) and Day 70 (Visit 9).

Number of Patients in Each Category of Clinical Global Impression of Change (CGI-C) in Overall PD Symptoms

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. 1 - Normal not ill, 2 - Borderline ill, 3 - Mildly ill, 4 - Moderately ill, 5 - Markedly ill, 6- Severely ill, 7 - Among the most extremely ill patients The CGI-C rates the patient's condition from 1 to 7: 1 - Very much improved, 2 - Much improved, 3 - Minimally improved, 4 - No change, 5 - Minimally worse, 6 - Much worse, 7 - Very much worse

Time frame: Clinician rated the patient´s global condition using CGI-S at baseline (Day 1, Visit 2) and CGI-C at Day 28 (Visit 6) and Day 42 (Visit 7).

Change From Baseline in Dyskinesia Scores Measured by the Kinesia 360 (Great Lakes Neurotechnologies, Inc) Wearable Dyskinesia Assessment System - Absolute Change From Baseline

The Kinesia 360 (Great Lakes Neurotechnologies, Inc) wearable dyskinesia assessment system was used to monitor dyskinesias. Sensors worn on the wrist and ankle combined with a mobile application continuously record data for assessment dyskinesia. Algorithms were used to detect symptoms from the motion sensors data and calculate a severity score (0 to 1 where score 0 corresponds to no dyskinesia and score 1 corresponds to dyskinesia) every 2 minutes. Wearable data collection of dyskinesia took place during a 2-day period prior to Visit 2 (Baseline), Visit 6 (Titration) and Visit 7 (Steady state). Outcome is presented as the mean ratio at baseline and absolute ratio change from baseline.

Time frame: Baseline - prior to Day 1 (Visit 2), Titration - prior to Day 28 (Visit 6), and Steady state prior to Day 42 (Visit 7).