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

Study Overview
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Brief Summary
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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.

Detailed Description
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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. Four 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 4-day period prior to the baseline visit (Day 1, Visit 2) and a 4-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).

Official Title
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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

Conditions
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Medication-Induced Dyskinesia

Intervention / Treatment
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* Drug: NLX-112
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. 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). 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). At least two 30-minute time periods from 9 am to 4 pm and at least 90 minutes total of each 24-hour period are indicated as ON with troublesome dyskinesia (according to the PD Home Dyskinesia Diary) prior to Day 1 (baseline, Visit 2). Patient (and/or caregiver) demonstrates ability to accurately complete the PD Home Dyskinesia Diary entries during the screening visit. Patient can read well enough to understand the informed consent document and other subject materials. 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: Patient has severe PD with a Hoehn and Yahr stage = 5. Patient has unstable medical status, prior brain surgery (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. 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 2 minutes of the patient standing up, compared to pressures obtained while in a supine 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. Patient has dementia (MMSE <20). Patient has clinically significant renal or liver disorder. 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. Any suicidal actions in the past 2 years (per investigator judgement i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behavior). 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). Patient has taken an anti-convulsant, an anti-psychotic (except quetiapine), pindolol, tertatolol or buspirone within 4 weeks of baseline (Day 1, Visit 2). Patient has taken any medication, within 4 weeks of baseline (Day 1, Visit 2) that inhibits or up-regulates CYP4503A4. Patient is concurrently participating in another investigational drug trial or has participated in another investigational drug trial within the past 3 months. Patient is at high risk of non-compliance in the Investigator's opinion.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind, randomized, placebo-controlled Phase 2a study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NLX-112<br>Patients will self-administer NLX-112 2 times each day, once in the morning and once in the evening. Up-titration over 4 weeks, maximal dose of 2 mg/day during 2 weeks, down-titration over 2 weeks. | Drug: NLX-112<br>* 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.<br>* Other names: (2E)-2-butenedioate;|
| Placebo Comparator: Placebo<br>Patients will self-administer placebo 2 times each day, once in the morning and once in the evening. Up-titration of number of tablets over 4 weeks, number of tablets equivalent to maximal dose of 2 mg/day NLX-112 during 2 weeks, down-titration over 2 weeks. | Drug: Placebo<br>* Placebo will be matching tablets (identical weight, shape and color) without NLX-112.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the safety and tolerability of NLX-112, titrated up to a maximum of 2 mg/day, compared to placebo during 8 weeks of daily treatment in PD patients with LID assess as number of Adverse events. | Number of 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). | Through study completion, an average of 10 weeks | 
| To evaluate the safety and tolerability of NLX-112, titrated up to a maximum of 2 mg/day, compared to placebo during 8 weeks of daily treatment in PD patients with LID as clinically significant changes from baseline in Electrocardiogram (ECG) | Number of reported clinically significant changes from baseline in Electrocardiogram (Rate, PR interval, QRS duration, QT, QTcB, and QTcF) | Through study completion, an average of 10 weeks | 
| To evaluate the safety and tolerability of NLX-112, titrated up to a maximum of 2 mg/day, compared to placebo during 8 weeks of daily treatment in PD patients with LID as clinically significant changes from baseline in Vital signs | Number of reported clinically significant changes from baseline in Vital signs (Systolic blood pressure (mmHg), diastolic blood pressure (mmHg), Heart rate, respiratory rate, body temperature) | Through study completion, an average of 10 weeks | 
| To evaluate the safety and tolerability of NLX-112, titrated up to a maximum of 2 mg/day, compared to placebo during 8 weeks of daily treatment in PD patients with LID as clinically significant changes from baseline in safety laboratory parameters | Number of reported clinically significant changes from baseline in safety laboratory parameters (Alanine aminotransferase (ALT) Albumin Alkaline phosphatase (ALP) Aspartate aminotransferase (AST) Bilirubin (total and conjugated) Calcium Chloride C-reactive protein (CRP) (screening only) Creatine phosphokinase (CPK) Creatinine (eGFR included) Gamma glutamyl transpeptidase (GGT) Glucose Phosphate Potassium Sodium Urea (nitrogen) Uric acid Hematocrit Hemoglobin (Hb) Platelet count Red blood cell (RBC) count White blood cell (WBC) count with differential count Mean corpuscular volume (MCV) Mean corpuscular hemoglobin (MCH) Mean corpuscular hemoglobin concentration (MCHC) Activated Partial Thromboplastin Time (APTT) Prothrombin Complex International Normalized Ratio (PK[INR]) Bilirubin Blood Erythrocytes Glucose Ketones Leucocytes Nitrites pH Albumin). | Through study completion, an average of 10 weeks | 
| To evaluate the safety and tolerability of NLX-112, titrated up to a maximum of 2 mg/day, compared to placebo during 8 weeks of daily treatment in PD patients with LID as clinically significant changes from baseline in Physical examinations | Number of clinically significant changes in physical examination investigated bygeneral appearance, head, ears, eyes, nose, throat, neck, skin, cardiovascular system, respiratory system, abdominal system, and nervous system. | Through study completion, an average of 10 weeks | 
| To evaluate the safety and tolerability of NLX-112, titrated up to a maximum of 2 mg/day, compared to placebo during 8 weeks of daily treatment in PD patients with LID as quantification of the severity of suicidal ideation and behavior. | Suicidal ideation/behavior as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS), questionnaire with no total score summation. | Through study completion, an average of 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the preliminary efficacy of NLX-112 treatment in reducing troublesome LID as measured with the Unified Dyskinesia Rating Scale (UDysRS). | Change from baseline at the final efficacy clinic visit (Day 42) in the Unified Dyskinesia Rating Scale (UDysRS) total score [Timeframe: Baseline to Day 42]. Patients will be challenged with 150% of their standard L-DOPA dose (maximum L DOPA dose 250 mg) 30 minutes prior to the first UDysRS assessment. Each item in the UDysRS is scored from 0 to 4, with a possible maximum total score of 104 which is most severe. | Baseline to Day 42 | 
| To assess the preliminary efficacy of NLX-112 treatment in reducing troublesome LID as measured with the Unified Dyskinesia Rating Scale (UDysRS) | Change from baseline in Unified Dyskinesia Rating Scale (UDysRS) total score at Day 28, after a 150% L DOPA dose challenge. Each item in the UDysRS is scored from 0 to 4, with a possible maximum total score of 104 which is most severe. | Baseline to Day 28 | 
| To assess the preliminary efficacy of NLX-112 treatment in reducing troublesome LID as measured with the Unified Dyskinesia Rating Scale (UDysRS) | Change from baseline in total objective score (Parts III, IV) of the Unified Dyskinesia Rating Scale (UDysRS) at Day 28 and Day 42, after a 150% L-DOPA dose challenge. Each item in the Unified Dyskinesia Rating Scale is scored from 0 to 4, with a possible maximum total score of 104. Higher scores mean a worse outcome. | Baseline to Day 28 and Day 42 | 
| To assess the preliminary efficacy of NLX-112 treatment in reducing troublesome LID based on changed score in patient reporting using Parkinson´s Disease (PD) Home Dyskinesia Diary. | 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. The electronic diary will be used to score 5 different conditions: ASLEEP; OFF; ON (i.e., adequate control of PD symptoms) without dyskinesia; ON with non-troublesome dyskinesia; ON with troublesome dyskinesia. | Baseline over study duration to Day 42 | 
| To assess the preliminary efficacy of NLX-112 treatment in reducing troublesome LID measured with the Unified Parkinson's Disease Rating Scale (UPDRS) (Part III, motor examination). | Change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) scores (Part III, motor examination). Each item in the UPDRS is scored from 0 to 4, with a possible maximum total score in part III of 56 which is most severe. | Baseline over study duration to Day 70 | 
| To assess the preliminary efficacy of NLX-112 treatment in reducing troublesome LID measured with the Unified Parkinson's Disease Rating Scale (UPDRS) combined scores (Parts I, II, III and IV). | Change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) combined scores (Parts I, II, III and IV). Each item in the UPDRS is scored from 0-1 or 0 to 4, with a possible maximum total score of 199 which is most severe. | Baseline over study duration to Day 70 | 
| To assess the preliminary efficacy of NLX-112 treatment in reducing troublesome LID measured as the Clinical Global Impression of Change (CGI-C) in overall Parkinson´s Disease symptoms. | Clinical Global Impression of Change (CGI-C) in overall Parkinsons´s Disease symptoms. 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. | Baseline over study duration to Day 42 | 
| To assess the preliminary efficacy of NLX-112 treatment in reducing troublesome LID measured with wearable dyskinesia assessment system. | Change from baseline in dyskinesia scores measured by the Kinesia 360 (Great Lakes Neurotechnologies, Inc) wearable dyskinesia assessment system. Dyskinesia symptom severity score on a 0 to 4 scale, where 0 is the absence of symptoms and 4 is the most severe. Measured in 2 minutes periods. | Baseline over study duration to Day 42 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LID, Levodopa, Dyskinesia, Parkinson´s disease, L-dopa, NLX-112, Befiradol