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

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

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) .

Study Overview

• Status: Completed
• Conditions: Idiopathic Parkinson Disease
• Intervention / Treatment: Drug: Placebo; Drug: Levodopa; Drug: CVXL-0107

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Maisons-Alfort, France, 94700
    • Clevexel Pharma

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed written Informed Consent
2. Male and female patient aged 40 -75 years
3. Clinical diagnosis of idiopathic PD according to the UK Parkinson's Disease Society Brain Bank Clinical Diagnosis Criteria
4. Advanced PD with clear daily motor fluctuations and dyskinesia with optimal levodopa-based therapy
5. At least 2 hours in "OFF" state per day including morning OFF
6. Predictable "OFF" in the morning on awakening prior to receiving morning dose of levodopa
7. 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
8. Patient with dyskinesia: MDS-UPDRS items 4.1 ("time spent with dyskinesia") and 4.2 ("functional impact of dyskinesia") scores ≥ 1 at Screening
9. Hoehn and Yahr stages of 2-4 in the "OFF" state at Screening
10. 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))
11. Anti-PD therapy intended to remain constant throughout the course of the study
12. Normal platelets count
13. Mini-mental state examination (MMSE)≥24 at Screening
14. PD patient treated by DBS can be included if surgery occurred at least one year before the study
15. Patient with health insurance
16. Female of childbearing potential with an effective contraception

Exclusion Criteria:

1. Any relevant neurologic or psychiatric disease, except idiopathic PD
2. Any secondary causes for Parkinsonism or other neurodegenerative disorder with Parkinsonism symptoms
3. Any neurosurgical intervention for PD planned during the study period
4. Neuroleptics and any D2-receptor antagonists within the last 3 months before Screening
5. Amantadine, Riluzole, dextromethorphan, apomorphine continuous infusion (pump), morphine, or memantine, during the last month before screening and during the study duration
6. History of psychosis or treatment with any antipsychotic drugs within the last 2 years
7. History of seizure or epilepsy, or treatment with anticonvulsant drugs within the last year
8. Any clinically significant unstable medical illness in the last month before randomization (e.g. unstable angina, unstable vascular disease etc)
9. Anti-cancer treatment within the 3 months before Screening
10. Treatment with anticoagulant drugs
11. Any clinically significant renal (serum creatinine level ≥1.5x ULN or dialysis) or hepatic (liver enzyme values≥2x ULN) disease
12. Any clinically significant condition that may compromise the safety of patient or the conduct of the study protocol according to Investigators' opinion.
13. Known genetic disorder of human UDP-glucuronosyltransferase
14. Participation in another trial with any investigational product within the last month before randomization or intake of any investigational product
15. Pregnant, breastfeeding or lactating female

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CVXL-0107 then cross-over to placebo; 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: Placebo; Drug: Levodopa; Drug: CVXL-0107
Placebo Comparator: Placebo then cross-over to CVXL-0107; 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: Placebo; Drug: Levodopa; Drug: CVXL-0107

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: CleveXel Pharma
• Investigators: Principal Investigator: Jean-Christophe Corvol, MD, PhD, CIC-Neurologie, bâtiment ICM, Hôpital Pitié-Salpêtrière, 47/83 Bd de l'Hôpital, 75013 Paris, France

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2016
• Primary Completion (Actual): June 1, 2017
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: December 7, 2015
• First Submitted That Met QC Criteria: December 22, 2015
• First Posted (Estimate): December 29, 2015

Study Record Updates

• Last Update Posted (Actual): July 24, 2017
• Last Update Submitted That Met QC Criteria: July 20, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Levodopa
• Other Study ID Numbers: CT-CVXL-0107-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No