Efficacy Phase IIa Study of CVXL-0107 in Advanced Parkinson's Disease

Study Overview
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Brief Summary
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CVXL-0107 a glutamate release inhibitor, has shown evidence of antiparkinsonian and antidyskinetic activity in a macaque model and has shown a significant effect on the UPDRS-III (Movement Disorder Society - Unified Parkinson's Disease Rating Scale) while ON, as well as an increase of ON-time without dyskinesia or without troublesome dyskinesia in a previous phase 2a proof of concept study. This study will confirm the efficacy of CVXL-0107 in combination with optimal dose of levodopa on motor symptoms of Parkinson's disease (PD) .

Detailed Description
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Phase IIa study, 1:1 randomized, double blind placebo- controlled, with cross-over. Each volunteer patient will be randomly assigned to receive CVXL-0107 or placebo as add-on PD therapy and crossed-over to the other arm in the second sequence of the study. They will be assessed during an acute levodopa challenge test with one intake of the study drug or placebo with a supra-optimal dose of levodopa after 2 weeks of daily treatment with the same study drug or placebo. Patients will be cross-overed to the other treatment and reassessed during a second acute levodopa challenge test after 2 weeks of daily treatment with the study drug or the placebo. The study will evaluate the anti-PD and the anti-dyskinesia efficacy of CVXL-0107 as measured by MDS-UPDRS part III (Movement Disorder Society - Unified Parkinson's Disease Rating Scale) and on levodopa-induced dyskinesia as measured by the AIMS (Abnormal Involuntary Movement Scale).

Official Title
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Double-Blind Randomized Placebo-Controlled Cross-Over Phase IIa Trial to Evaluate Efficacy of CVXL-0107 on Parkinson-Related Symptoms and Levodopa-Induced Dyskinesia in Advanced Parkinson's Disease Patients Using a Levodopa Challenge Test

Conditions
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Idiopathic Parkinson Disease

Intervention / Treatment
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* Drug: CVXL-0107
* Drug: Placebo
* Drug: Levodopa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written Informed Consent Male and female patient aged 40 -75 years Clinical diagnosis of idiopathic PD according to the UK Parkinson's Disease Society Brain Bank Clinical Diagnosis Criteria Advanced PD with clear daily motor fluctuations and dyskinesia with optimal levodopa-based therapy At least 2 hours in OFF state per day including morning OFF Predictable OFF in the morning on awakening prior to receiving morning dose of levodopa During an acute levodopa challenge test : Motor improvement of at least 30% on the MDS-UPDRS part III and AIMS score ≥ 1 at least two time points Patient with dyskinesia: MDS-UPDRS items 4.1 (time spent with dyskinesia) and 4.2 (functional impact of dyskinesia) scores ≥ 1 at Screening Hoehn and Yahr stages of 2-4 in the OFF state at Screening Stable doses and regimens of antiparkinsonian medications for at least the last month prior to randomization (levodopa, dopamine agonists and selective monoamine oxidase type B inhibitors (selegiline, rasagiline)) Anti-PD therapy intended to remain constant throughout the course of the study Normal platelets count Mini-mental state examination (MMSE)≥24 at Screening PD patient treated by DBS can be included if surgery occurred at least one year before the study Patient with health insurance Female of childbearing potential with an effective contraception Exclusion Criteria: Any relevant neurologic or psychiatric disease, except idiopathic PD Any secondary causes for Parkinsonism or other neurodegenerative disorder with Parkinsonism symptoms Any neurosurgical intervention for PD planned during the study period Neuroleptics and any D2-receptor antagonists within the last 3 months before Screening Amantadine, Riluzole, dextromethorphan, apomorphine continuous infusion (pump), morphine, or memantine, during the last month before screening and during the study duration History of psychosis or treatment with any antipsychotic drugs within the last 2 years History of seizure or epilepsy, or treatment with anticonvulsant drugs within the last year Any clinically significant unstable medical illness in the last month before randomization (e.g. unstable angina, unstable vascular disease etc) Anti-cancer treatment within the 3 months before Screening Treatment with anticoagulant drugs Any clinically significant renal (serum creatinine level ≥1.5x ULN or dialysis) or hepatic (liver enzyme values≥2x ULN) disease Any clinically significant condition that may compromise the safety of patient or the conduct of the study protocol according to Investigators' opinion. Known genetic disorder of human UDP-glucuronosyltransferase Participation in another trial with any investigational product within the last month before randomization or intake of any investigational product Pregnant, breastfeeding or lactating female

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CVXL-0107 then cross-over to placebo<br>Study drug (CVXL-0107) 4 times per day for 2 weeks on top of usual treatment for Parkinson disease, followed by one challenge test day: one intake of study drug on top of supraoptimal dose of levodopa. Cross-over to placebo 4 times per day for 2 weeks on top of usual treatment for Parkinson disease, followed by one challenge test day: one intake of placebo on top of supraoptimal dose of levodopa | Drug: CVXL-0107<br> <br> Drug: Placebo<br> <br> Drug: Levodopa<br> <br> |
| Placebo Comparator: Placebo then cross-over to CVXL-0107<br>Placebo 4 times per day for 2 weeks on top of usual treatment for Parkinson disease, followed by one challenge test day: one intake of placebo on top of supraoptimal dose of levodopa. Cross-over to study drug (CVXL-0107) 4 times per day for 2 weeks on top of usual treatment for Parkinson disease, followed by one challenge test day: one intake of study drug on top of supraoptimal dose of levodopa | Drug: CVXL-0107<br> <br> Drug: Placebo<br> <br> Drug: Levodopa<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in MDS-UPDRS part III (Movement Disorder Society - Unified Parkinson's Disease Rating Scale Part III) score. | CVXL-0107 and placebo | at visit 3 (day 15= challenge test day) and visit 4 (day 37= challenge test day): at baseline (before L-Dopa administration), then every 20 minutes during the first hour and then every 30 minutes during 5 hours. | 
| Change in AIMS ( Abnormal Involuntary Movement Scale) score | CVXL-0107 and placebo | at visit 3 (day 15= challenge test day) and visit 4 (day 37 = challenge test day): at baseline (before L-Dopa administration), then every 20 minutes during the first hour and then every 30 minutes during 5 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Clinical Treatment-Emergent Adverse Events [Safety and Tolerability] | Physical examination, vital signs | at visit 3 (day 14) and visit 4 (day 36) | 
| Hematology laboratory safety of CVXL-0107 | complete blood count | at visit 3 (day 14) and visit 4 (day 36) | 
| Hepatic laboratory safety of CVXL-0107 | aspartate transaminase, alanine transaminase, gamma-glutamyl-transpeptidase, alkaline phosphatase | at visit 3 (day 14) and visit 4 (day 36) | 
| Area Under the Curve [AUC] of CVXL-0107 concentrations | Blood samples at L-dopa intake and after 20', 40', 60', 90', 120', 240'. | at visit 3 (day 15= challenge test day) and visit 4 (day 37= challenge test day) | 
| Area Under the Curve [AUC] of levodopa concentrations | Blood samples at L-dopa intake and after 20', 40', 60', 90', 120', 240'. | at visit 3 (day 15= challenge test day) and visit 4 (day 37= challenge test day) | 
| Assessment of total daily ON time in Patients Diaries | Total ON-time | During 3 days, prior to visit 3 (days 11-13) and prior to visit 4 (days 33, 34, 35) | 
| Assessment of daily ON time without dyskinesia in Patients Diaries | ON-time without dyskinesia | During 3 days; prior to visit 3 (days 11-13) and prior to visit 4 (days 33, 34, 35) |